In [1]:
from IPython.display import HTML
HTML("""<style>{}</style>""".format(open("assets/css/custom.css").read()))
Out[1]:
In [2]:
import processors
print(processors.__version__)
3.0.3
In [3]:
from processors import *
from processors.visualization import JupyterVisualizer as viz

API = ProcessorsAPI(port=8881, keep_alive=True)
INFO - Using path given via $PROCESSORS_SERVER
INFO - Connection with server established!
INFO - Server version meets recommendations (v3.0.2)
In [4]:
import os

abstracts_dir = "/Users/gus/repos/ohsu-hackathon/OHSU_NLP_Hackathon/sentences_and_abstracts/CIViC_abstracts"

def annotate_documents(collection_dir):
    for f in os.listdir(collection_dir):
        file_path = os.path.join(collection_dir, f)
        text = open(file_path).read()
        doc = API.bionlp.annotate(text) 
        # use filename as the doc's id
        doc.id = os.path.splitext(f)[0]
        yield doc
In [5]:
#docs = annotate_documents(abstracts_dir)
In [6]:
def serialize_documents(collection):
    for doc in collection:
        #doc.id = os.path.splitext(doc.id)[0]
        with open("{}.json".format(doc.id), "w") as out_file:
            out_file.write(doc.to_JSON())
In [7]:
#serialize_documents(docs)
In [8]:
import json

def deserialize_doc_collection(serialized_docs_dir):
    for json_file in os.listdir(serialized_docs_dir):
        fpath = os.path.join(serialized_docs_dir, json_file)
        with open(fpath) as infile:
            text = infile.read()
        doc_dict = json.loads(text)
        doc = Document.load_from_JSON(doc_dict)
        # FIXED, but not released (ADD TEST)
        # py-processors v3.0.3 wasn't retrieving the doc id
        doc.id = os.path.splitext(json_file)[0]
        yield doc
In [9]:
abstracts = list(deserialize_doc_collection("serialized-abstracts"))
In [23]:
rules = """

taxonomy:
    - AdverseOutcome:
      - Disease:
        - Cancer

vars:
    aoTerms: lemma=/^(morbitity|mortality)$/
    diseaseTerms: lemma=/^(disease|disorder|infection|inflammation|syndrome|toxicity)$/
    cancerTerms: lemma=/^(cancer|leukemia|malignancy|metastasis|tumou?r)$/
    
rules:

    - name: "adverse-outcome-1"
      label: AdverseOutcome
      priority: 1
      type: token
      pattern: |
        # high morbitity
        (?<! [lemma=low]) [${ aoTerms }] |
        # poor prognosis, adverse outcome, etc.
        [lemma=/^(poor)$/] [lemma=/^(outcome|outlook|prognosis)$/] |
        # high risk of X
        [tag=JJ & !lemma=low]? [lemma=/^(risk)$/] (of [tag=/^(JJ|NN)/]+)?
        
    - name: "cancer-1"
      label: Cancer
      priority: 1
      type: token
      pattern: |
        # malignant, ovarian, breast, etc.
        [tag=/^(JJ|NN)/]*
        (
         # ex. cancer, tumor, etc.
         [ ${ cancerTerms } ] |
         # blastoma, melanoma, etc.
         [!tag=/^NNP/ & tag=/^NN/ & lemma=/oma$/]
        )
        # should not be followed by suppressor, etc.
        (?! [lemma=suppressor])    
        
    - name: "disease-1"
      label: Disease
      priority: 2+
      type: token
      pattern: |
        # leukopenia
        [tag=/^(JJ|NN)/]*
        (
         # leukopenia
         # give cancer rule precedence over this less general one 
         [tag=/^NN/ & lemma=/(pe)?[nm]ia$/ & !mention=Cancer] |
         # arthritis, periodontitis, etc.
         [tag=/^NN/ & lemma=/itis$/] |
         # ex. Familial platelet disorder
         [${ diseaseTerms }]
        ) 
        # should not be followed by suppressor, etc.
        (?! [lemma=suppressor])
    
"""

def extract_from_collection(collection):
    for doc in collection:
        mentions = API.odin.extract_from_document(doc, rules)
        for m in sorted(mentions, key=lambda x: (x.document.id, x.sentence, x.start), reverse=False):
            yield m
In [ ]:
def display_mentions(mentions):
    for m in mentions:
        print(m.document.id)
        viz.display_mention(m)
10224221
They may also provide prognostic information in a wide range of Cancercommon cancers .
10224221
Cyclin E may even be a target for treatment of Cancercancers in the future .
10383129
CancerInflammatory myofibroblastic tumor ( IMT ) is a relatively rare soft tissue tumor .
10383129
Inflammatory myofibroblastic tumor ( IMT ) is a relatively Cancerrare soft tissue tumor .
10383129
The reactive versus neoplastic pathogenesis of this Cancertumor is unresolved .
10408776
To investigate the nature of somatic von Hippel-Lindau ( VHL ) mutations , we analyzed 173 Cancerprimary sporadic human renal cell carcinomas for mutations of the VHL tumor suppressor gene , using polymerase chain reaction ( PCR ) and single-strand conformational polymorphism analysis ( SSCP ) of DNA .
10408776
VHL mutations were found only in the Cancernonpapillary renal cell carcinoma ( RCC ) subtype , as previously reported .
10408776
Thus , mutations resulting in truncated proteins may lead to a higher AdverseOutcomerisk of RCC in VHL patients .
10485475
CancerGastrointestinal stromal tumor ( GIST ) is the most common mesenchymal tumor of the gastrointestinal tract .
10485475
Gastrointestinal stromal tumor ( GIST ) is the most Cancercommon mesenchymal tumor of the gastrointestinal tract .
10485475
The patients with mutation positive GISTs showed more frequent recurrences ( P = 0.0005 ) and higher AdverseOutcomemortality ( P = 0.0001 ) than did those with mutation negative GISTs .
10547574
Expression of cyclins D1 and D2 , as well as cyclin dependent kinase 4 ( cdk4 ) , was investigated by means of immunohistochemistry in 455 Cancergastric cancer cases .
10547574
Additional western blotting was performed for four Cancerbreast cancer and four gastric cancer cell lines and 35 fresh frozen gastric cancer samples , to confirm the cyclin D1 , D2 , and cdk4 data .
10547574
Additional western blotting was performed for four breast cancer and four Cancergastric cancer cell lines and 35 fresh frozen gastric cancer samples , to confirm the cyclin D1 , D2 , and cdk4 data .
10547574
Additional western blotting was performed for four breast cancer and four gastric cancer cell lines and 35 Cancerfresh frozen gastric cancer samples , to confirm the cyclin D1 , D2 , and cdk4 data .
10547574
Cyclin D1 was restricted to the nucleus of Cancercancer cells with a few exceptions , whereas cyclin D2 was present in both cell compartments , but predominantly in the cytoplasm .
10547574
In the cyclin D2 cases , this correlated with greater age ( p = 0.0004 ) , better differentiation ( p = 0.0023 ) , greater depth of Cancercancer invasion ( p = 0 .
10547574
003 ) , the presence of Cancerlymph node metastasis ( p = 0.0014 ) , vascular invasion by cancer cells ( p < 0.0001 ) , and poor prognosis ( p < 0.0001 ) , while cyclin D1 did not correlate with any of these except age ( p = 0.00193 ) .
10547574
003 ) , the presence of lymph node metastasis ( p = 0.0014 ) , vascular invasion by Cancercancer cells ( p < 0.0001 ) , and poor prognosis ( p < 0.0001 ) , while cyclin D1 did not correlate with any of these except age ( p = 0.00193 ) .
10547574
003 ) , the presence of lymph node metastasis ( p = 0.0014 ) , vascular invasion by cancer cells ( p < 0.0001 ) , and AdverseOutcomepoor prognosis ( p < 0.0001 ) , while cyclin D1 did not correlate with any of these except age ( p = 0.00193 ) .
10547574
Multivariate analysis revealed cyclin D2 overexpression to be an independent prognostic factor , in addition to depth of Cancercancer invasion and lymph node status .
10547574
The results indicate that cyclin D2 up-regulation plays an important role in the progression and prognosis of Cancergastric cancer independently of cdk4 , whereas cyclin D1 overexpression does not .
10617473
Here , it is shown that heterozygous germ line mutations in hCHK2 occur in DiseaseLi-Fraumeni syndrome , a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene .
10617473
Here , it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome , a highly Cancerpenetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene .
10617473
These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to Cancersarcoma , breast cancer , and brain tumors , and they also provide a link between the central role of p53 inactivation in human cancer and the well defined G2 checkpoint in yeast .
10617473
These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma , Cancerbreast cancer , and brain tumors , and they also provide a link between the central role of p53 inactivation in human cancer and the well defined G2 checkpoint in yeast .
10617473
These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma , breast cancer , and Cancerbrain tumors , and they also provide a link between the central role of p53 inactivation in human cancer and the well defined G2 checkpoint in yeast .
10617473
These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma , breast cancer , and brain tumors , and they also provide a link between the central role of p53 inactivation in Cancerhuman cancer and the well defined G2 checkpoint in yeast .
10786679
We studied , in Cancerprimary breast tumors through direct cDNA sequencing of exons 2-11 , whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy ( 202 patients , of whom 55 % responded ) or up-front ( poly ) chemotherapy ( 41 patients , of whom 46 % responded ) .
10786679
We studied , in primary breast tumors through direct cDNA sequencing of exons 2-11 , whether TP53 gene mutations can predict response in patients with Diseaseadvanced disease to either first-line tamoxifen therapy ( 202 patients , of whom 55 % responded ) or up-front ( poly ) chemotherapy ( 41 patients , of whom 46 % responded ) .
10786679
TP53 mutations were detected in 90 of 243 ( 37 % ) Cancertumors , and one-fourth of these mutations resulted in a premature termination of the protein .
10786679
The mutations were observed in 32 % ( 65 of 202 ) of the Cancerprimary tumors of tamoxifen treated patients and in 61 % ( 25 of 41 ) of the primary tumors of the chemotherapy patients .
10786679
The mutations were observed in 32 % ( 65 of 202 ) of the primary tumors of tamoxifen treated patients and in 61 % ( 25 of 41 ) of the Cancerprimary tumors of the chemotherapy patients .
10786679
TP53 mutated and estrogen receptor negative ( < 10 fmol/mg protein ) Cancertumors appeared to be the most resistant phenotype .
10786679
In conclusion , TP53 gene mutation of the Cancerprimary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy .
10786679
In conclusion , TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with Diseasemetastatic breast disease to tamoxifen therapy .
10866302
The tumor suppressor gene PTEN is frequently mutated in Cancerdiverse human cancers and in autosomal dominant cancer predisposition disorders .
10866302
The tumor suppressor gene PTEN is frequently mutated in diverse human cancers and in Diseaseautosomal dominant cancer predisposition disorders .
10866302
The tumor suppressor gene PTEN is frequently mutated in diverse human cancers and in Cancerautosomal dominant cancer predisposition disorders .
10866302
To examine whether Cancertumor derived and germ-line-derived missense mutations inactivate PTEN lipid phosphatase function , we constructed 42 distinct types of PTEN missense mutations and expressed them in Escherichia coli .
11050000
Because there is no known genetic abnormality common to all patients with Cancermyeloma , it is important to understand how genetic heterogeneity may lead to differences in signal transduction , cell cycle , and response to therapy .
11050000
Model cell lines have been used to study the effect that mutations in p53 and ras can have on growth properties and responses of Cancermyeloma cells .
11050000
These data show that changes in ras or p53 can alter the Cancermyeloma cell response to IL-6 and demonstrate that the genetic background can alter therapeutic responses .
11070098
BACKGROUND : The DNA-repair enzyme O6-methylguanine-DNA methyltransferase ( MGMT ) inhibits the killing of Cancertumor cells by alkylating agents .
11070098
MGMT activity is controlled by a promoter ; methylation of the promoter silences the gene in Cancercancer , and the cells no longer produce MGMT .
11070098
We examined Cancergliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents .
11070098
We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the Cancertumor to alkylating agents .
11070098
METHODS : We analyzed the MGMT promoter in Cancertumor DNA by a methylation specific polymerase-chain-reaction assay .
11070098
The Cancergliomas were obtained from patients who had been treated with carmustine ( 1,3-bis ( 2-chloroethyl )-1-nitrosourea , or BCNU ) .
11070098
RESULTS : The MGMT promoter was methylated in Cancergliomas from 19 of 47 patients ( 40 percent ) .
11070098
This finding was associated with regression of the Cancertumor and prolonged overall and disease-free survival .
11070098
It was an independent and stronger prognostic factor than age , stage , Cancertumor grade , or performance status .
11070098
CONCLUSIONS : Methylation of the MGMT promoter in Cancergliomas is a useful predictor of the responsiveness of the tumors to alkylating agents .
11070098
CONCLUSIONS : Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the Cancertumors to alkylating agents .
11122430
The recognition of recurrent genetic alterations in Cancerspecific tumour types has provided the basis for the reclassification of certain soft tissue neoplasms , and molecular analysis of patient material has the potential to provide both diagnostic and prognostic information .
11122430
In this review , we evaluate the role of molecular genetic testing as the prospective ' gold standard ' for Cancersarcoma diagnosis .
11144931
CancerSpindle cell sarcomas often present the surgical pathologist with a considerable diagnostic challenge .
11144931
CancerMalignant peripheral nerve sheath tumor , leiomyosarcoma , fibrosarcoma , and monophasic synovial sarcoma may all appear similar histologically .
11144931
Malignant peripheral nerve sheath tumor , Cancerleiomyosarcoma , fibrosarcoma , and monophasic synovial sarcoma may all appear similar histologically .
11144931
Malignant peripheral nerve sheath tumor , leiomyosarcoma , Cancerfibrosarcoma , and monophasic synovial sarcoma may all appear similar histologically .
11144931
Malignant peripheral nerve sheath tumor , leiomyosarcoma , fibrosarcoma , and Cancermonophasic synovial sarcoma may all appear similar histologically .
11144931
The application of ancillary diagnostic modalities , such as immunohistochemistry and electron microscopy , may be helpful in the differentiation of these Cancertumors , but in cases in which these adjunctive techniques fail to demonstrate any more definitive evidence of differentiation , tumor categorization may remain difficult .
11144931
The application of ancillary diagnostic modalities , such as immunohistochemistry and electron microscopy , may be helpful in the differentiation of these tumors , but in cases in which these adjunctive techniques fail to demonstrate any more definitive evidence of differentiation , Cancertumor categorization may remain difficult .
11144931
Cytogenetic and molecular genetic characterization of Cancertumors have provided the basis for the application of molecular assays as the newest components of the diagnostic armamentarium .
11144931
Because the chromosomal translocation t ( X ; 18 ) has been observed repeatedly in Cancermany synovial sarcomas , it has been heralded as a diagnostic hallmark of synovial sarcoma .
11144931
Because the chromosomal translocation t ( X ; 18 ) has been observed repeatedly in many synovial sarcomas , it has been heralded as a diagnostic hallmark of Cancersynovial sarcoma .
11144931
To formally test the specificity of this translocation for the diagnosis of Cancersynovial sarcoma , RNA extracted from formalin fixed , paraffin embedded tissue from a variety of soft tissue and spindle cell tumors was evaluated for the presence of t ( X ; 18 ) by reverse transcriptase-polymerase chain reaction .
11144931
To formally test the specificity of this translocation for the diagnosis of synovial sarcoma , RNA extracted from formalin fixed , paraffin embedded tissue from a variety of soft tissue and Cancerspindle cell tumors was evaluated for the presence of t ( X ; 18 ) by reverse transcriptase-polymerase chain reaction .
11144931
Although 85 % of the Cancersynovial sarcomas studied demonstrated t ( X ; 18 ) , 75 % of the malignant peripheral nerve sheath tumors in our cohort also demonstrated this translocation .
11144931
Although 85 % of the synovial sarcomas studied demonstrated t ( X ; 18 ) , 75 % of the Cancermalignant peripheral nerve sheath tumors in our cohort also demonstrated this translocation .
11144931
We conclude that the translocation t ( X ; 18 ) is not specific to Cancersynovial sarcoma and discuss the implications of the demonstration of t ( X ; 18 ) in a majority of malignant peripheral nerve sheath tumors .
11144931
We conclude that the translocation t ( X ; 18 ) is not specific to synovial sarcoma and discuss the implications of the demonstration of t ( X ; 18 ) in a majority of Cancermalignant peripheral nerve sheath tumors .
11208838
PURPOSE : To determine the prognostic and predictive significance of p53 and K-ras mutations in patients with completely Cancerresected non-small-cell lung cancer ( NSCLC ) .
11208838
RESULTS : Four hundred eighty-eight patients were entered onto E3590 ; 197 Cancertumors were assessable for analysis .
11208838
Multivariate analysis revealed only age and Cancertumor stage to be significant prognostic factors , although there was a trend bordering on statistical significance for K-ras ( P = .066 ) .
11248153
BACKGROUND : The HER2 gene , which encodes the growth factor receptor HER2 , is amplified and HER2 is overexpressed in 25 to 30 percent of Cancerbreast cancers , increasing the aggressiveness of the tumor .
11248153
BACKGROUND : The HER2 gene , which encodes the growth factor receptor HER2 , is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers , increasing the aggressiveness of the Cancertumor .
11248153
METHODS : We evaluated the efficacy and safety of trastuzumab , a recombinant monoclonal antibody against HER2 , in women with Cancermetastatic breast cancer that overexpressed HER2 .
11248153
RESULTS : The addition of trastuzumab to chemotherapy was associated with a longer time to Diseasedisease progression ( median , 7.4 vs. 4.6 months ; P < 0.001 ) , a higher rate of objective response ( 50 percent vs. 32 percent , P < 0.001 ) , a longer duration of response ( median , 9.1 vs. 6.1 months ; P < 0.001 ) , a lower rate of death at 1 year ( 22 percent vs. 33 percent , P = 0.008 ) , longer survival ( median survival , 25.1 vs. 20.3 months ; P = 0.01 ) , and a 20 percent reduction in the risk of death .
11248153
RESULTS : The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression ( median , 7.4 vs. 4.6 months ; P < 0.001 ) , a higher rate of objective response ( 50 percent vs. 32 percent , P < 0.001 ) , a longer duration of response ( median , 9.1 vs. 6.1 months ; P < 0.001 ) , a lower rate of death at 1 year ( 22 percent vs. 33 percent , P = 0.008 ) , longer survival ( median survival , 25.1 vs. 20.3 months ; P = 0.01 ) , and a 20 percent reduction in the AdverseOutcomerisk of death .
11248153
CONCLUSIONS : Trastuzumab increases the clinical benefit of first-line chemotherapy in Cancermetastatic breast cancer that overexpresses HER2 .
11290608
Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of Cancerhuman malignancy .
11290608
An internal tandem duplication ( ITD ) of the juxtamembrane ( JM ) domain coding sequence of the FLT3 gene ( FLT3 and ITD ) is found in 20 % of patients with Canceracute myeloid leukemia ( AML ) and is strongly associated with leukocytosis and a poor prognosis .
11290608
An internal tandem duplication ( ITD ) of the juxtamembrane ( JM ) domain coding sequence of the FLT3 gene ( FLT3 and ITD ) is found in 20 % of patients with acute myeloid leukemia ( AML ) and is strongly associated with leukocytosis and a AdverseOutcomepoor prognosis .
11290608
On the other hand , mutations of the c-KIT gene , which have been found in Cancermast cell leukemia and AML , are clustered in 2 distinct regions , the JM domain and D816 within the activation loop .
11290608
This study was designed to analyze the mutation of D835 of FLT3 , which corresponds to D816 of c-KIT , in a large series of Cancerhuman hematologic malignancies .
11290608
Several kinds of missense mutations were found in 30 of the 429 ( 7.0 % ) AML cases , 1 of the 29 ( 3.4 % ) Diseasemyelodysplastic syndrome ( MDS ) cases , and 1 of the 36 ( 2.8 % ) acute lymphocytic leukemia patients .
11290608
Several kinds of missense mutations were found in 30 of the 429 ( 7.0 % ) AML cases , 1 of the 29 ( 3.4 % ) myelodysplastic syndrome ( MDS ) cases , and 1 of the 36 ( 2.8 % ) Canceracute lymphocytic leukemia patients .
11325447
BACKGROUND AND METHODS : TP53 gene mutation and expression of p53 have been described to influence the radiosensitivity of Cancertumour cells from head and neck carcinomas .
11325447
BACKGROUND AND METHODS : TP53 gene mutation and expression of p53 have been described to influence the radiosensitivity of tumour cells from head and Cancerneck carcinomas .
11325447
The present study was performed to evaluate whether TP53 mutation may influence the clinical outcome of head and Cancerneck cancer patients treated with radiotherapy or surgery .
11325447
RESULTS : The present analysis is based on 114 patients with Cancersquamous cell carcinoma of the larynx , pharynx and oral cavity diagnosed between March 1992 and October 1996 .
11325447
TP53 mutations were found in 45 patients ( 39 % ) and in patients receiving radiotherapy , TP53 mutation was highly associated with AdverseOutcomepoor prognosis .
11325447
CONCLUSIONS : A strong relationship was observed between TP53 mutation and AdverseOutcomepoor prognosis ( increased risk of loco-regional failure and death ) in head and neck cancer patients given primary radiotherapy but not surgery .
11325447
CONCLUSIONS : A strong relationship was observed between TP53 mutation and poor prognosis ( increased AdverseOutcomerisk of loco-regional failure and death ) in head and neck cancer patients given primary radiotherapy but not surgery .
11325447
CONCLUSIONS : A strong relationship was observed between TP53 mutation and poor prognosis ( increased risk of loco-regional failure and death ) in head and Cancerneck cancer patients given primary radiotherapy but not surgery .
11504908
Recent evidence places the FRAP and mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway , which is up-regulated in Cancermultiple cancers because of loss of the PTEN tumor suppressor gene .
11504908
We performed biological and biochemical studies to determine whether CancerPTEN deficient cancer cells are sensitive to pharmacologic inhibition of FRAP and mTOR by using the rapamycin derivative CCI-779 .
11504908
In vitro and in vivo studies of isogenic PTEN ( +/+ ) and PTEN (-/-) mouse cells as well as Cancerhuman cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP and mTOR inhibition .
11504908
Enhanced Cancertumor growth caused by constitutive activation of Akt in PTEN ( +/+ ) cells also was reversed by CCI-779 treatment , indicating that FRAP and mTOR functions downstream of Akt in tumorigenesis .
11504908
These results provide rationale for testing FRAP and mTOR inhibitors in CancerPTEN null human cancers .
11505222
The von Hippel-Lindau ( VHL ) tumour suppressor gene is commonly mutated in Cancerrenal cell carcinoma of clear cell type ( CCRCC ) .
11505222
We analysed DNA from Cancertumour and nontumoural kidney tissue from 195 CCRCC patients .
11535556
The role of a polymorphism at position 72 of the tumor suppressor gene TP53 in the development of Cancercervical cancer is not well established .
11535556
We investigated a possible association between TP53 polymorphism and Cancercervical cancer in a Peruvian population with high prevalence of HPV infection .
11535556
We investigated a possible association between TP53 polymorphism and cervical cancer in a Peruvian population with high prevalence of DiseaseHPV infection .
11535556
HPV status and TP53 polymorphism were determined for 119 cases of Cancerinvasive cervical cancer and 127 control women from Peru .
11535556
DiseaseHPV infection was detected by PCR of cervical cells or tumor biopsies .
11535556
HPV infection was detected by PCR of cervical cells or Cancertumor biopsies .
11535556
Associations between TP53 polymorphism , DiseaseHPV infection , and cervical cancer were assessed using logistic regression .
11535556
Associations between TP53 polymorphism , HPV infection , and Cancercervical cancer were assessed using logistic regression .
11535556
Women homozygotes for arginine had a 2.2-fold increased AdverseOutcomerisk ( 95 % confidence interval : 0.6-7 .6 ) for cervical cancer .
11535556
Women homozygotes for arginine had a 2.2-fold increased risk ( 95 % confidence interval : 0.6-7 .6 ) for Cancercervical cancer .
11535556
Similarly increased AdverseOutcomerisks were found when restricting analysis to HPV positive women only .
11535556
Our results can not rule out an association between the TP53 polymorphism at codon 72 , DiseaseHPV infection , and the etiology of cervical cancer .
11535556
Our results can not rule out an association between the TP53 polymorphism at codon 72 , HPV infection , and the etiology of Cancercervical cancer .
11536052
Mutations in the von Hippel-Lindau ( VHL ) gene are frequently detected in Cancerhuman sporadic renal cell carcinoma ( RCC ) .
11536052
Mutations in the VHL gene were found in 54 % of Cancerclear cell renal cell carcinomas ( CCRCC ) and in 18 % of chromophilic cancers but in no chromophobe cancers or oncocytomas ( P = 0.016 ) .
11536052
Mutations in the VHL gene were found in 54 % of clear cell renal cell carcinomas ( CCRCC ) and in 18 % of Cancerchromophilic cancers but in no chromophobe cancers or oncocytomas ( P = 0.016 ) .
11536052
Mutations in the VHL gene were found in 54 % of clear cell renal cell carcinomas ( CCRCC ) and in 18 % of chromophilic cancers but in no Cancerchromophobe cancers or oncocytomas ( P = 0.016 ) .
11536052
Mutations in the VHL gene were found in 54 % of clear cell renal cell carcinomas ( CCRCC ) and in 18 % of chromophilic cancers but in no chromophobe cancers or Canceroncocytomas ( P = 0.016 ) .
11536052
In 5/6 patients the wild-type allele was lost in the Cancertumor samples , suggesting a causal role for the mutations in RCC .
11536052
Multiple mutations in VHL were found in 17 Cancertumors out of 47 tumors with the VHL mutation .
11536052
Multiple mutations in VHL were found in 17 tumors out of 47 Cancertumors with the VHL mutation .
11585760
The FLT3 gene is mutated by an internal tandem duplication ( ITD ) in 20-25 % of adults with Canceracute myeloid leukemia ( AML ) .
11585760
A AdverseOutcomepoor prognosis of the relatively young FLT3 ( ITD/-) adults ( median age , 37 years ) , despite treatment with current dose-intensive regimens , suggests that new treatment modalities , such as therapy with a FLT3 tyrosine kinase inhibitor , are clearly needed for this group of patients .
11595686
We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in Cancerovarian cancer patients .
11595686
EXPERIMENTAL DESIGN : One hundred seventy-eight Cancerovarian carcinomas , snap frozen and stored at -80 degrees C , were analyzed for mutations of the p53 gene ( exons 2-11 ) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry ( monoclonal antibody DO7 ) .
11595686
RESULTS : p53 mutations were found in 56 % ( 99 of 178 ) of the Cancertumors , and 62 % of these were located in evolutionary highly conserved domains of the gene .
11595686
CONCLUSIONS : p53 alterations correlate significantly with resistance to platinum based chemotherapy , early relapse , and shortened overall survival in Cancerovarian cancer patients in univariate analysis .
11607825
CancerSynovial sarcomas are high grade spindle cell tumors that are divided into two major histologic subtypes , biphasic and monophasic , according to the respective presence or absence of a well developed glandular epithelial component .
11607825
Synovial sarcomas are Cancerhigh grade spindle cell tumors that are divided into two major histologic subtypes , biphasic and monophasic , according to the respective presence or absence of a well developed glandular epithelial component .
11607825
Ongoing work on the SYT-SSX fusion and Cancersynovial sarcoma should yield a variety of data of broader biological interest , in areas such as BRM and Polycomb group function and dysfunction , transcriptional targets of SYT-SSX proteins and their native counterparts , differential gene regulation by SYT-SSX1 and SYT-SSX2 , control of glandular morphogenesis , among others .
11704842
All trans retinoic acid ( ATRA ) is able to induce complete remission ( CR ) in almost all patients with Canceracute promyelocytic leukemia ( APL ) through in vivo differentiation of APL blasts .
11751510
PURPOSE : SMAD4 ( also called Dpc4 ) is a tumor suppressor in the TGF-beta signaling pathway that is genetically inactivated in approximately 55 % of all Cancerpancreatic adenocarcinomas .
11751510
We investigated whether prognosis after surgical resection for Cancerinvasive pancreatic adenocarcinoma is influenced by SMAD4 status .
11751510
EXPERIMENTAL DESIGN : Using immunohistochemistry , we characterized the SMAD4 protein status of 249 Cancerpancreatic adenocarcinomas resected from patients who underwent pancreaticoduodenectomy ( Whipple resection ) at The Johns Hopkins Hospital , Baltimore , MD , between 1990 and 1997 .
11751510
The SMAD4 gene status of 56 of 249 ( 22 % ) Cancerpancreatic carcinomas was also determined .
11751510
A multivariate Cox proportional hazards model assessed the AdverseOutcomerelative risk of mortality associated with SMAD4 status , adjusting for known prognostic variables .
11751510
RESULTS : Patients with Cancerpancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival ( unadjusted median survival was 19.2 months as compared with 14.7 months in patients with pancreatic cancers lacking SMAD4 protein expression ; P = 0.03 ) .
11751510
RESULTS : Patients with pancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival ( unadjusted median survival was 19.2 months as compared with 14.7 months in patients with Cancerpancreatic cancers lacking SMAD4 protein expression ; P = 0.03 ) .
11751510
This SMAD4 survival benefit persisted after adjustment for prognostic factors including Cancertumor size , margins , lymph node status , pathological stage , blood loss , and use of adjuvant chemoradiotherapy .
11751510
The relative hazard of AdverseOutcomemortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 ( 95 % confidence interval , 1.01-1 .83 ; P = 0.04 ) .
11751510
The relative hazard of mortality for Cancercancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 ( 95 % confidence interval , 1.01-1 .83 ; P = 0.04 ) .
11751510
CONCLUSION : Patients undergoing Whipple resection for Cancerpancreatic adenocarcinoma survive longer if their cancers express SMAD4 .
11751510
CONCLUSION : Patients undergoing Whipple resection for pancreatic adenocarcinoma survive longer if their Cancercancers express SMAD4 .
11782370
CancerSynovial sarcomas are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation .
11782370
Synovial sarcomas are Canceraggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation .
11782370
Previous studies have suggested that patients with CancerSYT-SSX2 tumors do better than those with SYT-SSX1 tumors , but the study groups were too limited to be conclusive .
11782370
Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with CancerSYT-SSX1 tumors , but the study groups were too limited to be conclusive .
11782370
To address this issue more definitively , we collected data on SYT-SSX fusion type , pathology , and clinical course in a retrospective multi-institutional study of 243 patients ( age range , 6-82 ) with Cancersynovial sarcoma .
11782370
SYT-SSX1 and SYT-SSX2 fusions were detected in 147 Cancertumors ( 61 % ) and 91 tumors ( 37 % ) , respectively .
11782370
SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors ( 61 % ) and 91 Cancertumors ( 37 % ) , respectively .
11782370
Overall survival was significantly better among SYT-SSX2 cases ( P = 0.03 ) , among cases localized at diagnosis ( P < 0.0001 ) , and among patients with Cancerprimary tumors < 5 cm in greatest dimension ( P = 0.01 ) .
11782370
The impact of fusion type on survival remained significant when stratified for Cancerprimary tumor size ( P = 0.03 ) but was no longer significant when stratified for disease status at presentation .
11782370
The impact of fusion type on survival remained significant when stratified for primary tumor size ( P = 0.03 ) but was no longer significant when stratified for Diseasedisease status at presentation .
11782370
This may reflect the tendency for patients with CancerSYT-SSX1 tumors to present more often with metastatic disease ( P = 0.05 ) .
11782370
This may reflect the tendency for patients with SYT-SSX1 tumors to present more often with Diseasemetastatic disease ( P = 0.05 ) .
11782370
Cox regression identified Diseasedisease status ( P < 0.0001 ) and primary tumor size ( P = 0.04 ) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors .
11782370
Cox regression identified disease status ( P < 0.0001 ) and Cancerprimary tumor size ( P = 0.04 ) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors .
11782370
Within the subset of patients with Diseaselocalized disease at diagnosis ( n = 202 ) , the median and 5-year survival for the SYT-SSX1 and the SYT-SSX2 groups were 9.2 years and 61 % versus 13.7 years and 77 % , respectively .
11782370
Patients whose Cancertumors contained the SYT-SSX2 fusion ( P = 0.08 ) or were smaller ( P = 0.12 ) showed a trend toward better survival by log-rank test , whereas tumor histology had no impact ( P = 0.8 ) .
11782370
Patients whose tumors contained the SYT-SSX2 fusion ( P = 0.08 ) or were smaller ( P = 0.12 ) showed a trend toward better survival by log-rank test , whereas Cancertumor histology had no impact ( P = 0.8 ) .
11782370
In a Cox regression analysis considering all of the factors , SYT-SSX fusion type emerged as the only independent significant factor ( P = 0.04 ) for overall survival within the subset of 133 patients with Diseaselocalized disease at diagnosis who had information on all of the factors .
11782370
Among other comparisons , there was a strong association of fusion type and morphology ( P < 0.001 ) , with almost all of the CancerSYT-SSX2 tumors showing absence of glandular differentiation ( monophasic histology ) and almost all of the biphasic tumors containing SYT-SSX1 .
11782370
Among other comparisons , there was a strong association of fusion type and morphology ( P < 0.001 ) , with almost all of the SYT-SSX2 tumors showing absence of glandular differentiation ( monophasic histology ) and almost all of the Cancerbiphasic tumors containing SYT-SSX1 .
11782370
Overall , SYT-SSX fusion type appears to be the single most significant prognostic factor by multivariate analysis in patients with Diseaselocalized disease at diagnosis .
11782370
In addition , the associations of SYT-SSX fusion type with patient sex and Cancertumor epithelial differentiation point to interesting mechanistic biological differences .
11792751
BACKGROUND : CancerHuman pancreatic adenocarcinomas are highly resistant to chemotherapy .
11792751
The p16 tumor-suppressor protein is inactivated in more than 90 % of Cancerhuman pancreatic cancers .
11792751
The p16 protein transcriptionally inhibits expression of Cancerretinoblastoma tumor-suppressor gene pRB .
11792751
Because pRB normally prevents apoptosis , we investigated whether pRB is involved in resistance to chemotherapy induced apoptosis in Cancerpancreatic cancer cells .
11792751
The Cancerhuman pancreatic tumor cell line Capan-1 ( pRB +/p16-) was stably transfected with p16 to functionally inactivate pRB .
11792751
RESULTS : pRB was overexpressed in Cancerpancreatic ductal adenocarcinomas but was hardly detectable in other pancreatic malignancies , chronic pancreatitis , or nontransformed human pancreatic tissue .
11792751
RESULTS : pRB was overexpressed in pancreatic ductal adenocarcinomas but was hardly detectable in Cancerother pancreatic malignancies , chronic pancreatitis , or nontransformed human pancreatic tissue .
11792751
RESULTS : pRB was overexpressed in pancreatic ductal adenocarcinomas but was hardly detectable in other pancreatic malignancies , Diseasechronic pancreatitis , or nontransformed human pancreatic tissue .
11792751
The effect was specific to pRB depletion because two Cancerother human pancreatic cancer cell lines that retained high pRB expression after p16 transfection were resistant to chemotherapy induced apoptosis .
11792751
CONCLUSIONS : Overexpression of pRB is associated with Cancerhuman pancreatic duct-cell cancer and may allow pancreatic cancer cells to evade chemotherapy induced apoptosis .
11792751
CONCLUSIONS : Overexpression of pRB is associated with human pancreatic duct-cell cancer and may allow Cancerpancreatic cancer cells to evade chemotherapy induced apoptosis .
11793370
Mutations of the von Hippel-Lindau ( VHL ) gene are considered critical for the initiation of Cancerclear cell renal cell carcinoma .
11793370
In this study , the association of VHL mutations with Cancertumour cell proliferation , angiogenesis , and clinical outcome was analysed in 113 clear cell renal cell carcinomas .
11793370
In this study , the association of VHL mutations with tumour cell proliferation , angiogenesis , and clinical outcome was analysed in 113 Cancerclear cell renal cell carcinomas .
11793370
The degree of angiogenesis and Cancertumour cell proliferation was immunohistochemically determined by counting microvessels ( microvessel density , anti-CD34 antibody ) and cells with proliferating activity ( Ki-67 labelling index , MIB-1 antibody ) .
11793370
CancerTumour grade , stage , microvessel density , and tumour cell proliferation were not associated with VHL alterations .
11793370
Tumour grade , stage , microvessel density , and Cancertumour cell proliferation were not associated with VHL alterations .
11793370
These findings may indicate that ' loss-of-function ' VHL mutations are involved in the progression of a Cancerclear cell renal cell carcinoma subset , whereas regulation of angiogenesis and proliferation of renal carcinoma in vivo is apparently not directly influenced by VHL alterations .
11793370
These findings may indicate that ' loss-of-function ' VHL mutations are involved in the progression of a clear cell renal cell carcinoma subset , whereas regulation of angiogenesis and proliferation of Cancerrenal carcinoma in vivo is apparently not directly influenced by VHL alterations .
11830488
DiseaseFamilial platelet disorder with predisposition to acute myelogenous leukemia ( FPD and AML ) is an autosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML .
11830488
Familial platelet disorder with predisposition to Canceracute myelogenous leukemia ( FPD and AML ) is an autosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML .
11830488
Familial platelet disorder with predisposition to acute myelogenous leukemia ( FPD and AML ) is an Diseaseautosomal dominant familial platelet disorder characterized by thrombocytopenia and a propensity to develop AML .
11830488
Familial platelet disorder with predisposition to acute myelogenous leukemia ( FPD and AML ) is an autosomal dominant familial platelet disorder characterized by Diseasethrombocytopenia and a propensity to develop AML .
11830488
While haploinsufficiency of RUNX1 causes FPD and AML in some families ( deletions and frameshifts ) , mutant RUNX1 proteins ( missense and nonsense ) may also inhibit wild-type RUNX1 , possibly creating a higher propensity to develop Cancerleukemia .
11830488
This is consistent with the hypothesis that a second mutation has to occur , either in RUNX1 or another gene , to cause Cancerleukemia among individuals harboring RUNX1 FPD and AML mutations and that the propensity to acquire these additional mutations is determined , at least partially , by the initial RUNX1 mutation .
12000708
CancerGastrointestinal stromal tumors ( GISTs ) are mesenchymal neoplasms of the gut wall that express the receptor tyrosine kinase KIT .
12000708
This approach was used to assess the frequency of KIT mutations in 13 morphologically benign , incidentally discovered , GISTs identified at autopsy , endoscopy , or laparotomy for Diseaseunrelated disease .
12000708
Eleven of the 13 Cancertumors had sequence confirmed mutations in KIT , including 10 mutations in exon 11 ( 77 % ) and one mutation in exon 9 ( 7.7 % ) .
12000708
The remaining two Cancertumors were wild type for exons 9 , 11 , and 17 ; one of these was also analyzed for exon 13 and was wild type in this exon as well .
12000708
In addition , the overall frequency of mutations in the Cancerincidental tumors ( 85 % ) did not differ significantly from that we previously reported in a series of 72 advanced and metastatic GISTs ( 86 % ) , strongly supporting the view that activating mutations in KIT are acquired very early in the development of most GISTs .
12060124
RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and Diseaselymphoblastic leukaemia .
12060124
We have identified a unique point mutation of the RUNX1 gene ( A107P ) in members of a family with autosomal dominant inheritance of Diseasethrombocytopenia .
12060124
One member has developed Diseaseacute myeloid leukaemia ( AML ) .
12075054
BACKGROUND : The survival of patients with Cancerdiffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors .
12075054
BACKGROUND : The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the Cancertumors .
12075054
We used the gene expression profiles of these Cancerlymphomas to develop a molecular predictor of survival .
12075054
METHODS : Biopsy samples of Cancerdiffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities .
12075054
A molecular predictor of AdverseOutcomerisk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients .
12075054
RESULTS : Three gene expression subgroups -- germinal-center B-cell-like , activated B-cell-like , and type 3 Cancerdiffuse large-B-cell lymphoma -- were identified .
12075054
Two common oncogenic events in Cancerdiffuse large-B-cell lymphoma , bcl-2 translocation and c-rel amplification , were detected only in the germinal-center B-cell-like subgroup .
12075054
CONCLUSIONS : DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for Cancerdiffuse large-B-cell lymphoma .
12237773
In order to evaluate the clinical relevance of SMAD4 deletion , gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 Cancercolorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy .
12237773
These data are consistent with the previous observation that patients whose Cancercancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy .
12237773
Moreover , these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion , thereby suggesting SMAD4 as a predictive marker in Cancercolorectal cancer .
12237773
This data also indicate that integrity of this component of the transforming growth factor-beta and bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with Cancercolorectal cancer .
12357354
FLT3 is a receptor tyrosine kinase that may play a role in a significant proportion of Cancerleukemias .
12357354
In addition to being aberrantly expressed in Canceracute leukemias , activating mutations of the FLT3 gene have been found in patients with AML , myelodysplastic syndrome ( MDS ) and more rarely , ALL .
12357354
In addition to being aberrantly expressed in acute leukemias , activating mutations of the FLT3 gene have been found in patients with AML , Diseasemyelodysplastic syndrome ( MDS ) and more rarely , ALL .
12357354
Internal tandem duplications ( ITDs ) of the FLT3 gene have been detected in 17-34 % of patients with AML and portend a AdverseOutcomepoor prognosis for these patients .
12357354
We examined the inhibitory effects of AG1296 on FLT3 and ITDs isolated from AML patients in the IL-3-dependent cell line , Ba/F3 , as well as in Cancerprimary leukemia samples from AML patients .
12357354
These findings suggest that inhibiting the activity of FLT3 may have a therapeutic value in some Cancerleukemias expressing FLT3 and ITDs .
12432043
We investigated whether levels of cyclin E in the Cancertumor correlated with survival among patients with breast cancer .
12432043
We investigated whether levels of cyclin E in the tumor correlated with survival among patients with Cancerbreast cancer .
12432043
METHODS : CancerTumor tissue from 395 patients with breast cancer was assayed for cyclin E , cyclin D1 , cyclin D3 , and the HER-2 and neu oncogene with the use of Western blot analysis .
12432043
METHODS : Tumor tissue from 395 patients with Cancerbreast cancer was assayed for cyclin E , cyclin D1 , cyclin D3 , and the HER-2 and neu oncogene with the use of Western blot analysis .
12432043
Immunohistochemical assessments of cyclin E were also made of 256 Cancertumors .
12432043
We sought correlations between levels of these molecular markers and Diseasedisease specific and overall survival .
12432043
A high level of the low-molecular-weight isoforms of cyclin E , as detected by Western blotting , correlated strongly with Diseasedisease specific survival whether axillary lymph nodes were negative or positive for metastases ( P < 0.001 ) .
12432043
Among 114 patients with stage I Cancerbreast cancer , none of the 102 patients with low levels of cyclin E in the tumor had died of breast cancer by five years after diagnosis , whereas all 12 patients with a high level of low-molecular-weight cyclin E had died of breast cancer within that period .
12432043
Among 114 patients with stage I breast cancer , none of the 102 patients with low levels of cyclin E in the Cancertumor had died of breast cancer by five years after diagnosis , whereas all 12 patients with a high level of low-molecular-weight cyclin E had died of breast cancer within that period .
12432043
Among 114 patients with stage I breast cancer , none of the 102 patients with low levels of cyclin E in the tumor had died of Cancerbreast cancer by five years after diagnosis , whereas all 12 patients with a high level of low-molecular-weight cyclin E had died of breast cancer within that period .
12432043
Among 114 patients with stage I breast cancer , none of the 102 patients with low levels of cyclin E in the tumor had died of breast cancer by five years after diagnosis , whereas all 12 patients with a high level of low-molecular-weight cyclin E had died of Cancerbreast cancer within that period .
12432043
In multivariate analysis , a high total cyclin E level or high levels of the low-molecular-weight forms of cyclin E were significantly correlated with AdverseOutcomepoor outcome .
12432043
The hazard ratio for death from Cancerbreast cancer for patients with high total cyclin E levels as compared with those with low total cyclin E levels was 13.3 -- about eight times as high as the hazard ratios associated with other independent clinical and pathological risk factors .
12432043
The hazard ratio for death from breast cancer for patients with high total cyclin E levels as compared with those with low total cyclin E levels was 13.3 -- about eight times as high as the hazard ratios associated with other independent clinical and AdverseOutcomepathological risk factors .
12432043
CONCLUSIONS : Levels of total cyclin E and low-molecular-weight cyclin E in Cancertumor tissue , as measured by Western blot assay , correlate strongly with survival in patients with breast cancer .
12432043
CONCLUSIONS : Levels of total cyclin E and low-molecular-weight cyclin E in tumor tissue , as measured by Western blot assay , correlate strongly with survival in patients with Cancerbreast cancer .
12483530
All of the Cancermyeloma cell lines we tested express both N-ras and K-ras , but not H-ras .
12509970
In this study , we focused on p53 mutations in specific regions , including DNA binding surface regions , to clarify the correlation between mutations within the specific regions of p53 and clinical outcomes of patients with Canceroral cancers .
12509970
We analyzed p53 mutations in 121 Cancerfresh primary oral squamous cell carcinomas ( SCCs ) by polymerase chain reaction-single-strand conformation polymorphism or a yeast functional assay .
12509970
Mutation of p53 was not associated with any clinicopathological parameters ; however , Cancertumors containing specific p53 mutations , e.g. DNA binding surface regions ( L2 , L3 and the LSH motif ) and conserved regions ( II-V ) , had significantly poorer prognoses than tumors with mutations outside of those regions .
12509970
Mutation of p53 was not associated with any clinicopathological parameters ; however , tumors containing specific p53 mutations , e.g. DNA binding surface regions ( L2 , L3 and the LSH motif ) and conserved regions ( II-V ) , had significantly poorer prognoses than Cancertumors with mutations outside of those regions .
12509970
Moreover , locoregional failure , Cancerlymph node metastasis and the occurrence of subsequent distant metastasis were also significantly associated with mutations within DNA binding surface regions .
12509970
Moreover , locoregional failure , lymph node metastasis and the occurrence of Cancersubsequent distant metastasis were also significantly associated with mutations within DNA binding surface regions .
12517791
CancerMost prostate cancers ( PCs ) become resistant to combined androgen blockade therapy with surgical or medical castration and antiandrogens after several years .
12517791
Some of these refractory PCs regress after discontinuation of Diseaseantiandrogen administration [ antiandrogen withdrawal syndrome ( AWS ) ] .
12559175
The serine threonine kinase gene AURORA-A is commonly amplified in Cancerepithelial malignancies .
12559175
Here we show that elevated Aurora-A expression at levels that reflect Cancercancer associated gene amplification overrides the checkpoint mechanism that monitors mitotic spindle assembly , inducing resistance to the chemotherapeutic agent paclitaxel ( Taxol ) .
12559175
Consistent with this conclusion , elevated Aurora-A expression causes resistance to apoptosis induced by Taxol in a Cancerhuman cancer cell line .
12660384
BACKGROUND : DiseaseIdiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction .
12660384
Recent reports of responses to imatinib in patients with the Diseasesyndrome suggested that an activated kinase such as ABL , platelet derived growth factor receptor ( PDGFR ) , or KIT , all of which are inhibited by imatinib , might be the cause .
12660384
METHODS : We treated 11 patients with the Diseasehypereosinophilic syndrome with imatinib and identified the molecular basis for the response .
12660384
The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the Diseasesyndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months .
12660384
CONCLUSIONS : The Diseasehypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion .
12727991
A series of 88 conventional follicular and CancerHurthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry .
12727991
Forty-nine percent of Cancerconventional follicular carcinomas had RAS mutations , 36 % had PAX8-PPAR gamma rearrangement , and only one ( 3 % ) had both .
12727991
In Cancerfollicular adenomas , 48 % had RAS mutations , 4 % had PAX8-PPAR gamma rearrangement , and 48 % had neither .
12727991
CancerFollicular carcinomas with PAX8-PPAR gamma typically showed immunoreactivity for galectin-3 but not for HBME-1 , tended to present at a younger patient age and be smaller size , and were almost always overtly invasive .
12727991
In contrast , Cancerfollicular carcinomas with RAS mutations most often displayed an HBME-1-positive and galectin-3-negative immunophenotype and were either minimally or overtly invasive .
12727991
CancerHurthle cell tumors infrequently had PAX8-PPAR gamma rearrangement or RAS mutations .
12727991
These results suggest that Cancerconventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement .
12777976
Flavopiridol has been shown to mimic , in part , the effect of the cell cycle control gene p16 , which is frequently lost or mutated in Cancermalignant melanoma , making it an ideal candidate for targeted therapy in this disease .
12777976
Flavopiridol has been shown to mimic , in part , the effect of the cell cycle control gene p16 , which is frequently lost or mutated in malignant melanoma , making it an ideal candidate for targeted therapy in this Diseasedisease .
12777976
In these studies we investigated the effect of flavopiridol , at various concentrations , on the growth and gene expression of nine Cancerhuman melanoma cell lines with intact , absent or mutated p16 .
12777976
A cytostatic effect of flavopiridol on the growth of six Cancermelanoma cell lines with a mutated or non expressed p16 ( p16-) was seen at low concentrations of flavopiridol ( mean 50 % inhibitory concentration [ IC ( 50 ) ] = 12.5 nM ) , while the three melanoma cell lines with intact p16 ( p16+ ) required higher concentrations ( mean IC ( 50 ) = 25 nM ) to produce this effect .
12777976
A cytostatic effect of flavopiridol on the growth of six melanoma cell lines with a mutated or non expressed p16 ( p16-) was seen at low concentrations of flavopiridol ( mean 50 % inhibitory concentration [ IC ( 50 ) ] = 12.5 nM ) , while the three Cancermelanoma cell lines with intact p16 ( p16+ ) required higher concentrations ( mean IC ( 50 ) = 25 nM ) to produce this effect .
12777976
These data indicate that flavopiridol in low , clinically achievable concentrations may have significant cytostatic effects , particularly in Cancerp16- melanoma cells , and may provide new molecular based therapies for melanoma , particularly when combined with agents that target anti-apoptotic mechanisms .
12777976
These data indicate that flavopiridol in low , clinically achievable concentrations may have significant cytostatic effects , particularly in p16- melanoma cells , and may provide new molecular based therapies for Cancermelanoma , particularly when combined with agents that target anti-apoptotic mechanisms .
12840112
To examine the AdverseOutcomerisk of lung cancer associated with the codon 72 , intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case-control studies was undertaken .
12840112
To examine the risk of Cancerlung cancer associated with the codon 72 , intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case-control studies was undertaken .
12840112
The principle outcome measure was the odds ratio ( OR ) for the AdverseOutcomerisk of lung cancer using homozygosity of the ' wild-type allele ' as the reference group .
12840112
The principle outcome measure was the odds ratio ( OR ) for the risk of Cancerlung cancer using homozygosity of the ' wild-type allele ' as the reference group .
12840112
Data from 13 studies detailing the relationship between Cancerlung cancer and the codon 72 polymorphism of TP53 and three studies examining the intron 3 and 6 polymorphisms of TP53 were analysed .
12840112
The ORs of Cancerlung cancer associated with the Pro Pro and Pro carrier genotypes of codon 72 were 1.18 [ 95 % confidence interval ( CI ) 0.99-1 .41 ] and 1.02 ( 95 % CI 0.86-1 .20 ) , respectively .
12840112
The ORs of Cancerlung cancer associated with homozygous and variant allele carrier genotypes of the intron 6 ( MspI RFLP ) polymorphism were 1.13 ( 95 % CI 0.55-2 .27 ) and 1.30 ( 95 % CI 0.75-2 .26 ) and of the intron 3 ( 16 bp duplication ) polymorphism were 1.50 ( 95 % CI 0.76-2 .97 ) and 1.11 ( 95 % CI 0.53-2 .35 ) , respectively .
12840112
Although polymorphic variations in TP53 represent attractive candidate susceptibility alleles for Cancerlung cancer the results from this analysis provide little support for this hypothesis .
12840112
Additional well designed studies based on sample sizes commensurate with the detection of small AdverseOutcomegenotypic risks may allow a more definitive conclusion .
12865922
Germline mutations in the LKB1 and DiseaseSTK11 tumour suppressor gene cause Peutz-Jeghers syndrome ( PJS ) , a rare dominant disorder .
12865922
Germline mutations in the LKB1 and STK11 tumour suppressor gene cause Peutz-Jeghers syndrome ( PJS ) , a Diseaserare dominant disorder .
12865922
In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions , PJS is associated with an AdverseOutcomeincreased risk of tumours at multiple sites .
12865922
In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions , PJS is associated with an increased risk of Cancertumours at multiple sites .
12865922
Here we report the analysis of the LKB1 and STK11 locus in a series of 33 PJS families , and estimation of Cancercancer risks in carriers and noncarriers .
12865922
Here we report the analysis of the LKB1 and STK11 locus in a series of 33 PJS families , and estimation of cancer AdverseOutcomerisks in carriers and noncarriers .
12865922
In carriers of LKB1 and STK11 mutations , the AdverseOutcomerisk of cancer was markedly elevated .
12865922
In carriers of LKB1 and STK11 mutations , the risk of Cancercancer was markedly elevated .
12865922
The AdverseOutcomerisk of developing any cancer in carriers by age 65 years was 47 % ( 95 % CI : 27-73 % ) with elevated risks of both gastrointestinal and breast cancer .
12865922
The risk of developing any Cancercancer in carriers by age 65 years was 47 % ( 95 % CI : 27-73 % ) with elevated risks of both gastrointestinal and breast cancer .
12865922
The risk of developing any cancer in carriers by age 65 years was 47 % ( 95 % CI : 27-73 % ) with AdverseOutcomeelevated risks of both gastrointestinal and breast cancer .
12865922
The risk of developing any cancer in carriers by age 65 years was 47 % ( 95 % CI : 27-73 % ) with elevated risks of both gastrointestinal and Cancerbreast cancer .
12865922
PJS with germline mutations in LKB1 and STK11 are at a very high relative and AdverseOutcomeabsolute risk of multiple gastrointestinal and nongastrointestinal cancers .
12865922
PJS with germline mutations in LKB1 and STK11 are at a very high relative and absolute risk of multiple gastrointestinal and Cancernongastrointestinal cancers .
12865922
To obtain precise estimates of AdverseOutcomerisk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1 and STK11 negative cases , as this group is likely to be heterogeneous .
12949711
BACKGROUND & AIMS : CancerMost gastrointestinal stromal tumors ( GISTs ) have gain-of-function mutations of c-kit receptor tyrosine kinase ( KIT ) gene , but some GISTs do not .
14504092
We recently described a subset of patients with a myeloproliferative variant of Diseasehypereosinophilic syndrome ( MHES ) characterized by elevated serum tryptase levels , increased atypical mast cells in the bone marrow , tissue fibrosis , and the presence of the fusion tyrosine kinase , FIP1L1-PDGFRalpha , which is a therapeutic target of imatinib mesylate .
14514923
AIMS : To evaluate the usefulness of molecular markers in predicting histopathological and clinical response to preoperative high dose chemotherapy ( HDCT ) and survival of patients with Canceradvanced gastric cancer .
14514923
METHODS : In a phase II trial , 25 patients with Cancermetastatic gastric cancer received preoperative tandem HDCT consisting of etoposide , cisplatin , and mitomycin , followed by autologous bone marrow transplantation to achieve surgical resectability .
14514923
Samples before and after treatment , from normal and Cancertumour tissue , were characterised histopathologically , and both p53 and BAX expression was analysed by immunohistochemistry .
14514923
Pretreatment formalin fixed , paraffin wax embedded samples from normal and Cancertumour tissue were microdissected , and the extracted DNA was preamplified using improved primer extension preamplification polymerase chain reaction .
14514923
Patients 's sex or age , Cancertumour location or stage , lymph node status , Lauren classification , MSI , or LOH did not influence duration of survival significantly in this high risk population .
14514923
Patients 's sex or age , tumour location or stage , lymph node status , Lauren classification , MSI , or LOH did not influence duration of survival significantly in this AdverseOutcomehigh risk population .
14514923
CONCLUSION : Positive p53 immunostaining and p53 mutation status in Cancerpretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT .
14514923
CONCLUSION : Positive p53 immunostaining and p53 mutation status in pretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with Canceradvanced gastric cancer treated by preoperative HDCT .
14583498
CancerGlioblastoma multiforme ( GBM ) frequently involves amplification and alteration of the epidermal growth factor receptor ( EGFR ) gene , resulting in overexpression of varied mutations , including the most common mutation , EGFRvIII , as well as wild-type EGFR ( EGFRwt ) .
14612939
The cyclin D2 gene is overexpressed in a subset of Cancergastric carcinoma .
14612939
To determine whether hypomethylation of cyclin D2 is involved in stomach carcinogenesis , we studied methylation of CpG islands in the cyclin D2 gene by methylation specific PCR in 34 Cancergastric carcinoma specimens , 21 corresponding non neoplastic mucosae , and 8 gastric carcinoma cell lines .
14612939
To determine whether hypomethylation of cyclin D2 is involved in stomach carcinogenesis , we studied methylation of CpG islands in the cyclin D2 gene by methylation specific PCR in 34 gastric carcinoma specimens , 21 corresponding non neoplastic mucosae , and 8 Cancergastric carcinoma cell lines .
14612939
We also measured levels of cyclin D2 mRNA in 23 of the Cancergastric carcinoma cases and in the gastric carcinoma cell lines .
14612939
We also measured levels of cyclin D2 mRNA in 23 of the gastric carcinoma cases and in the Cancergastric carcinoma cell lines .
14612939
Hypomethylation of the cyclin D2 promoter was found in 24 ( 71 % ) of the 34 Cancertumor tissues and in 6 ( 29 % ) of the 21 corresponding non neoplastic mucosa , the incidence being significantly different ( p = 0.002 ; Fisher 's exact test ) .
14612939
Moreover , hypomethylation of cyclin D2 was more common in stage III and IV Cancertumors than in stage I and II tumors ( p = 00.014 ; Fisher 's exact test ) .
14612939
Moreover , hypomethylation of cyclin D2 was more common in stage III and IV tumors than in stage I and II Cancertumors ( p = 00.014 ; Fisher 's exact test ) .
14612939
These results suggest that DNA hypomethylation is a mechanism underlying the increased expression of cyclin D2 in Cancercancer cells and that demethylation of cyclin D2 may be involved in development and progression of gastric carcinoma .
14612939
These results suggest that DNA hypomethylation is a mechanism underlying the increased expression of cyclin D2 in cancer cells and that demethylation of cyclin D2 may be involved in development and progression of Cancergastric carcinoma .
14645423
PURPOSE : CancerMost gastrointestinal stromal tumors ( GISTs ) express constitutively activated mutant isoforms of KIT or kinase platelet derived growth factor receptor alpha ( PDGFRA ) that are potential therapeutic targets for imatinib mesylate .
14645423
In patients with GISTs harboring exon 11 KIT mutations , the partial response rate ( PR ) was 83.5 % , whereas patients with Cancertumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8 % ( P = .0006 ) and 0.0 % ( P < .0001 ) , respectively .
14645423
Patients whose Cancertumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation .
14645423
Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose Cancertumors expressed either exon 9 KIT mutations or had no detectable kinase mutation .
14679114
BACKGROUND : Trastuzumab provides significant clinical benefits in CancerHER2 positive metastatic breast cancer patients when administered in combination with chemotherapy .
14679114
Chemotherapy has also been shown to be beneficial in some patients with Canceradvanced non-small-cell lung cancer ( NSCLC ) .
14679114
Addition of trastuzumab to gemcitabine-cisplatin was well tolerated , side-effects were as expected , and trastuzumab did not exacerbate the Diseaseknown toxicity of gemcitabine and cisplatin .
14726385
The presence of p53 mutation or deletion predicts for poor response to conventional therapy in Cancerchronic lymphocytic leukemia ( CLL ) .
14726387
Activating mutations of FMS like tyrosine kinase 3 ( FLT3 ) are present in approximately 30 % of patients with de novo Canceracute myeloid leukemia ( AML ) and are associated with lower cure rates from standard chemotherapy based treatment .
14726387
Successful FLT3 inhibition can also improve survival in mouse models of FLT3 activated Cancerleukemia .
14726387
DiseaseCEP-701-related toxicities were minimal .
14726387
Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3 activating mutations and indicate that CEP-701 holds promise as a novel , molecularly targeted therapy for this Diseasedisease .
14726504
PURPOSE : To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT and enhancer binding protein alpha ( C/EBP alpha ) in a large prospective series of younger adults with Canceracute myeloid leukemia ( AML ) and normal cytogenetics .
14726504
CONCLUSION : Mutant CEBPA predicts favorable prognosis and may improve AdverseOutcomerisk stratification in AML patients with normal cytogenetics .
14967075
HER2 is reported to be overexpressed in 20 % of cases of Cancernon-small-cell lung cancer ( NSCLC ) , principally adenocarcinoma .
14967075
HER2 is reported to be overexpressed in 20 % of cases of non-small-cell lung cancer ( NSCLC ) , principally Canceradenocarcinoma .
14967075
Trastuzumab is a monoclonal antibody against HER2 that , when combined with a taxane , improves survival compared with chemotherapy alone in Canceradvanced breast cancer .
14967075
Patients with CancerHER2 positive tumors ( 2+ or 3+ ) were initially randomized to either single-agent trastuzumab or docetaxel .
14967075
Only 13 patients ( 19 % ) had DiseaseHER2 positive disease ; all 13 enrolled in the efficacy trial .
14967075
The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8 % of cases , Diseasestable disease in 23 % , progression in 46 % , and nonassessable disease in 23 % .
14967075
The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8 % of cases , stable disease in 23 % , progression in 46 % , and Diseasenonassessable disease in 23 % .
14993230
PURPOSE : To evaluate the antitumor activity and Diseasetoxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor .
14993230
PURPOSE : To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with Cancerchemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor .
14993230
PURPOSE : To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose Cancertumors express the epidermal growth factor receptor .
14993230
Patients were required to have EGFr expression demonstrated on formalin fixed Cancerparaffin embedded tumor tissue by immunohistochemical staining before study participation .
14993230
All were assessable for Diseasetoxicity and response .
14993230
The most commonly encountered grade 3 to 4 adverse events , regardless of relationship to study drug , were an acne like skin rash , predominantly on the face and upper torso ( 86 % with any grade ; 18 % with grade 3 ) , and a composite of Diseaseasthenia , fatigue , malaise , or lethargy ( 56 % with any grade , 9 % with grade 3 ) .
14993230
Neither diarrhea nor Diseaseneutropenia were dose limiting in any of the 57 patients treated .
14993230
Twenty-one additional patients had Diseasestable disease or minor responses .
14993230
The median survival in these previously treated patients with Cancerchemotherapy-refractory colorectal cancer is 6.4 months .
14993230
CONCLUSION : Cetuximab on this once-weekly schedule has modest activity and is well tolerated as a single agent in patients with Cancerchemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor .
14993230
CONCLUSION : Cetuximab on this once-weekly schedule has modest activity and is well tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose Cancertumors express the epidermal growth factor receptor .
14993230
Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this Diseasedisease .
15118125
Receptor tyrosine kinase genes were sequenced in Cancernon small cell lung cancer ( NSCLC ) and matched normal tissue .
15118125
Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 Cancerunselected tumors from Japan and 1 of 61 from the United States .
15118125
Treatment with the EGFR kinase inhibitor gefitinib ( Iressa ) causes Cancertumor regression in some patients with NSCLC , more frequently in Japan .
15118125
EGFR mutations were found in Canceradditional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib , but not in gefitinib-insensitive tumors or cell lines .
15118125
EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a Cancerlung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib , but not in gefitinib-insensitive tumors or cell lines .
15118125
EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib , but not in Cancergefitinib-insensitive tumors or cell lines .
15138475
Antioestrogen treatment by tamoxifen is a well established adjuvant therapy for oestrogen receptor-alpha ( ERalpha ) Cancerpositive breast cancer .
15138475
Despite ERalpha expression some Cancertumours do not respond to tamoxifen and we therefore delineated the potential link between the cell cycle regulator and ERalpha co-factor , cyclin D1 , and tamoxifen response in a material of 167 postmenopausal breast cancers arranged in a tissue array .
15138475
Despite ERalpha expression some tumours do not respond to tamoxifen and we therefore delineated the potential link between the cell cycle regulator and ERalpha co-factor , cyclin D1 , and tamoxifen response in a material of 167 Cancerpostmenopausal breast cancers arranged in a tissue array .
15138475
Interestingly in the 55 strongly ERalpha positive samples with moderate or low cyclin D1 levels , patients responded to tamoxifen treatment whereas the 46 patients with highly ERalpha positive and cyclin D1 overexpressing Cancertumours did not show any difference in survival between tamoxifen and no treatment .
15138475
Survival in untreated patients with Cancercyclin D1 high tumours was slightly better than for patients with cyclin D1 low and moderate tumours .
15138475
Survival in untreated patients with cyclin D1 high tumours was slightly better than for patients with cyclin D1 low and Cancermoderate tumours .
15138475
However , there was a clearly increased AdverseOutcomerisk of death in the cyclin D1 high group compared to an age matched control population .
15138475
Our results suggest that cyclin D1 overexpression predicts for tamoxifen treatment resistance in Cancerbreast cancer , which is line with recent experimental data using breast cancer cell lines and overexpression systems .
15138475
Our results suggest that cyclin D1 overexpression predicts for tamoxifen treatment resistance in breast cancer , which is line with recent experimental data using Cancerbreast cancer cell lines and overexpression systems .
15146165
CancerGastrointestinal stromal tumors ( GISTs ) are KIT expressing spindle cell , epithelioid and rarely pleomorphic mesenchymal tumors .
15146165
Gastrointestinal stromal tumors ( GISTs ) are KIT expressing spindle cell , epithelioid and rarely Cancerpleomorphic mesenchymal tumors .
15146165
Recently , gain-of-function mutations in exon 18 ( activation loop ) and exon 12 ( juxtamembrane domain ) of the PDGFRA were identified in Cancersuch tumors .
15146165
Low mitotic activity , < or = 5 mitoses/50HPF was detected in 81 % of analyzed GISTs including larger , > 5 Cancercm tumors .
15194504
The resistance to the tyrosine kinase inhibitor imatinib in BCR and CancerABL positive leukemias is mostly associated with mutations in the kinase domain of BCR and ABL , which include the most prevalent mutations E255K and T315I .
15217946
Kinase activity has been implicated in the pathophysiology of Cancermany tumors , including small-cell lung carcinoma ( SCLC ) .
15217946
Kinase activity has been implicated in the pathophysiology of many tumors , including Cancersmall-cell lung carcinoma ( SCLC ) .
15217946
Autocrine or paracrine activation of c-kit by its ligand has been postulated for Cancerlung cancer , but this receptor can also be activated by mutations of the c-kit gene .
15217946
CONCLUSIONS : In our series , the expression of c-kit and its mutational status failed to appear relevant or to have a significant impact on survival ; this makes the therapeutic approach with an inhibitor of tyrosine kinase more difficult in SCLC until a sure demonstration of c-kit implication is obtained for this Cancertumor .
15324695
The ErbB2 targeting antibody , trastuzumab ( Herceptin ) , has remarkable therapeutic efficacy in certain patients with ErbB2 overexpressing Cancertumors .
15324695
Reducing PTEN in Cancerbreast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo .
15324695
Patients with CancerPTEN deficient breast cancers had significantly poorer responses to trastuzumab based therapy than those with normal PTEN .
15448205
CancerHuman stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder ( MPD ) that evolves to acute myeloid leukemia and/or lymphoma .
15448205
DiseaseHuman stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder ( MPD ) that evolves to acute myeloid leukemia and/or lymphoma .
15448205
Human stem cell leukemia-lymphoma syndrome usually presents itself as a Diseasemyeloproliferative disorder ( MPD ) that evolves to acute myeloid leukemia and/or lymphoma .
15448205
Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder ( MPD ) that evolves to Canceracute myeloid leukemia and/or lymphoma .
15448205
Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder ( MPD ) that evolves to acute myeloid leukemia and/or Cancerlymphoma .
15448205
The Diseasesyndrome associated with t ( 8 ; 13 ) ( p11 ; q12 ) results in expression of the ZNF198-fibroblast growth factor receptor ( FGFR ) 1 fusion tyrosine kinase .
15448205
Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this Diseasedisease .
15448205
Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a Diseasemyeloproliferative syndrome in mice that recapitulated the human MPD phenotype .
15448205
Based in part on these data , PKC412 was administered to a patient with t ( 8 ; 13 ) ( p11 ; q12 ) and was efficacious in treatment of Diseaseprogressive myeloproliferative disorder with organomegaly .
15448205
Therefore , PKC412 may be a useful therapy for treatment of Diseasehuman stem cell leukemia-lymphoma syndrome .
15448205
Therefore , PKC412 may be a useful therapy for treatment of Cancerhuman stem cell leukemia-lymphoma syndrome .
15486187
PURPOSE : The predictive value of topoisomerase-II alpha ( topo-II ) has been evaluated in Canceradvanced breast cancer patients randomly treated with single-agent doxorubicin or docetaxel .
15486187
EXPERIMENTAL DESIGN : CancerPrimary tumor samples from patients enrolled in a randomized , phase III clinical trial comparing single-agent doxorubicin ( 75 mg/m ( 2 ) q3wks ) with docetaxel ( 100 mg/m ( 2 ) q3wks ) were collected and topo-II status was evaluated by immunohistochemistry ( clone KiS1 ) .
15486187
With increasing topo-II , the favorable OR for overall response to docetaxel compared with doxorubicin decreases to become not significant in patients with Cancertopo-II tumor content > 10 % .
15486187
( b ) Overall response to doxorubicin is significantly lower than overall response to docetaxel ( OR , 0.17 ; 95 % confidence interval , 0.04-0 .64 ; P = 0.009 ) but with a significant interaction term for doxorubicin treated patients with Cancertopo-II tumor content > 10 % ( OR , 8.31 ; 95 % confidence interval , 1.86-37 .03 ; P = 0.05 ) .
15555571
" CancerPericytoma with t ( 7 ; 12 ) " is a newly defined soft tissue tumor characterized by fusion of the ACTB and GLI genes through the translocation t ( 7 ; 12 ) ( p22 ; q13 ) .
15555571
" Pericytoma with t ( 7 ; 12 ) " is a newly defined Cancersoft tissue tumor characterized by fusion of the ACTB and GLI genes through the translocation t ( 7 ; 12 ) ( p22 ; q13 ) .
15597105
The proto-oncogene RAS , coding for a 21 kDa protein ( p21 ) , is mutated in 20 % of Cancerlung cancer .
15597105
However , the literature remains controversial on its prognostic significance for survival in Cancerlung cancer .
15597105
Published studies on Cancerlung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search .
15597105
In total , 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with Cancernon-small-cell lung cancer ( NSCLC ) and not the only one dealing with small-cell-lung cancer ( SCLC ) .
15597105
In total , 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer ( NSCLC ) and not the only one dealing with Cancersmall-cell-lung cancer ( SCLC ) .
15597105
The combined HR was 1.35 ( 95 % CI : 1.16-1 .56 ) , showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and , particularly , in Canceradenocarcinomas ( ADC ) ( HR 1.59 ; 95 % CI 1.26-2 .02 ) and in studies using PCR ( HR 1.40 ; 95 % CI 1.18-1 .65 ) but not in studies using IHC ( HR 1.08 ; 95 % CI 0.86-1 .34 ) .
15626738
FLT3 ( fms like tyrosine kinase 3 ) is constitutively activated in about 30 % of patients with Canceracute myeloid leukemia ( AML ) and represents a disease specific molecular marker .
15626738
FLT3 ( fms like tyrosine kinase 3 ) is constitutively activated in about 30 % of patients with acute myeloid leukemia ( AML ) and represents a Diseasedisease specific molecular marker .
15630448
Genes crucial for Cancercancer development can be mutated via various mechanisms , which may reflect the nature of the mutagen .
15630448
In Cancerthyroid papillary carcinomas , mutations of genes coding for effectors along the MAPK pathway are central for transformation .
15630448
BRAF point mutation is most common in Cancersporadic tumors .
15630448
By contrast , radiation induced Cancertumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1 .
15630448
The AKAP9-BRAF fusion was preferentially found in radiation induced Cancerpapillary carcinomas developing after a short latency , whereas BRAF point mutations were absent in this group .
15630448
These data indicate that in Cancerthyroid cancer , radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions , whereas in sporadic forms of the disease , effectors along the same pathway are activated predominantly by point mutations .
15630448
These data indicate that in thyroid cancer , radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions , whereas in sporadic forms of the Diseasedisease , effectors along the same pathway are activated predominantly by point mutations .
15647370
Mutations in genes that encode components of the phosphatidyl-inositol 3-kinase ( PI3-kinase ) signaling pathway are common in Cancerhuman cancer .
15647370
The recent discovery of nonrandom somatic mutations in the PIK3CA gene of Cancermany human tumors suggests an oncogenic role for the mutated enzyme .
15659725
METHODS : We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with Cancerprimary acute myelogenous leukemia ( AML ) .
15659725
We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the Diseasedisease .
15659725
It was associated with a wide spectrum of morphologic subtypes of the Diseasedisease , a normal karyotype , and responsiveness to induction chemotherapy , but not with recurrent genetic abnormalities .
1568170
The cytogenetic findings in 31 Cancerliposarcomas from 26 patients are reported .
1568170
Four Cancerother tumors did not grow .
1568170
The well differentiated Cancerliposarcomas were characterized by telomeric associations , large marker chromosomes and ring chromosomes , and in some cases , double minutes .
1568170
The Cancerpleomorphic liposarcomas contained very high clonal chromosomal numbers with near-tetraploid modes and numerous variable , often unidentifiable , chromosomal abnormalities .
1568170
The Cancermyxoid liposarcomas were characterized primarily by a t ( 12 ; 16 ) ( q13 ; p11 ) as the sole abnormality or additional changes .
1568170
These results indicate that cytogenetic findings may provide a new criterion , not only for establishing the diagnosis of Cancerliposarcoma , but also for differentiating confusing histologic types of liposarcoma and these lesions from other types of sarcomas .
1568170
These results indicate that cytogenetic findings may provide a new criterion , not only for establishing the diagnosis of liposarcoma , but also for differentiating confusing histologic types of Cancerliposarcoma and these lesions from other types of sarcomas .
1568170
These results indicate that cytogenetic findings may provide a new criterion , not only for establishing the diagnosis of liposarcoma , but also for differentiating confusing histologic types of liposarcoma and these lesions from other types of Cancersarcomas .
15696205
BACKGROUND : Somatic mutations in the gene for the epidermal growth factor receptor ( EGFR ) are found in Canceradenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib ( Iressa ) and erlotinib ( Tarceva ) .
15696205
CancerLung adenocarcinomas also harbor activating mutations in the downstream GTPase , KRAS , and mutations in EGFR and KRAS appear to be mutually exclusive .
15696205
We screened 60 Cancerlung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS .
15728811
Mutations of the epidermal growth factor receptor ( EGFR ) gene have been identified in specimens from patients with Cancernon-small-cell lung cancer who have a response to anilinoquinazoline EGFR inhibitors .
15728811
Here we report the case of a patient with EGFR-mutant , gefitinib responsive , Canceradvanced non-small-cell lung cancer who had a relapse after two years of complete remission during treatment with gefitinib .
15728811
The DNA sequence of the EGFR gene in his Cancertumor biopsy specimen at relapse revealed the presence of a second point mutation , resulting in threonine-to-methionine amino acid change at position 790 of EGFR .
15737014
BACKGROUND : CancerLung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib ( Iressa ) or erlotinib ( Tarceva ) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor ( EGFR ) .
15737014
METHODS AND FINDINGS : We show that in two of five patients with acquired resistance to gefitinib or erlotinib , progressing Cancertumors contain , in addition to a primary drug sensitive mutation in EGFR , a secondary mutation in exon 20 , which leads to substitution of methionine for threonine at position 790 ( T790M ) in the kinase domain .
15737014
CancerTumor cells from a sixth patient with a drug sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation .
15737014
Tumor cells from a sixth patient with a drug sensitive EGFR mutation whose Cancertumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation .
15737014
This mutation was not detected in Canceruntreated tumor samples .
15737014
Moreover , no Cancertumors with acquired resistance had KRAS mutations , which have been associated with primary resistance to these drugs .
15737014
Biochemical analyses of transfected cells and growth inhibition studies with Cancerlung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib .
15737014
CONCLUSION : In patients with Cancertumors bearing gefitinib- or erlotinib sensitive EGFR mutations , resistant subclones containing an additional EGFR mutation emerge in the presence of drug .
15737014
This observation should help guide the search for more effective therapy against a specific subset of Cancerlung cancers .
15746676
OBJECTIVE : A difference in survival rates between black and white patients with Cancercancer of the corpus uteri is well established .
15746676
This study was conducted to determine whether the overexpression of HER2 and neu oncogene is associated with AdverseOutcomepoor outcome in uterine serous papillary endometrial cancer , which is a highly aggressive variant of endometrial cancer , and whether a racial difference in the frequency of HER2 and neu overexpression may contribute to the disparity in endometrial cancer survival .
15746676
This study was conducted to determine whether the overexpression of HER2 and neu oncogene is associated with poor outcome in Canceruterine serous papillary endometrial cancer , which is a highly aggressive variant of endometrial cancer , and whether a racial difference in the frequency of HER2 and neu overexpression may contribute to the disparity in endometrial cancer survival .
15746676
This study was conducted to determine whether the overexpression of HER2 and neu oncogene is associated with poor outcome in uterine serous papillary endometrial cancer , which is a highly aggressive variant of Cancerendometrial cancer , and whether a racial difference in the frequency of HER2 and neu overexpression may contribute to the disparity in endometrial cancer survival .
15746676
This study was conducted to determine whether the overexpression of HER2 and neu oncogene is associated with poor outcome in uterine serous papillary endometrial cancer , which is a highly aggressive variant of endometrial cancer , and whether a racial difference in the frequency of HER2 and neu overexpression may contribute to the disparity in Cancerendometrial cancer survival .
15746676
STUDY DESIGN : Immunohistochemical evaluation was used to examine HER2 and neu expression in paraffin blocks from 27 women with stage IA to IV Canceruterine serous papillary endometrial cancer .
15746676
Univariable analysis was performed and followed by multivariable analysis with Cox 's proportional hazard model to evaluate whether HER2 and neu expression was associated with AdverseOutcomepoor outcome in uterine serous papillary endometrial cancer .
15746676
Univariable analysis was performed and followed by multivariable analysis with Cox 's proportional hazard model to evaluate whether HER2 and neu expression was associated with poor outcome in Canceruterine serous papillary endometrial cancer .
15746676
Earlier deaths from Canceruterine serous papillary endometrial cancer were seen among heavy HER2 and neu expressers ( P = .002 ) , black patients ( P = .04 ) , and patients < or = 65 years old ( P = .04 ) .
15746676
CONCLUSION : Overexpression of HER2 and neu in Canceruterine serous papillary endometrial cancer is an independent variable that is associated with poor outcome , occurs more frequently in black women , and may contribute to racial disparity in survival .
15746676
CONCLUSION : Overexpression of HER2 and neu in uterine serous papillary endometrial cancer is an independent variable that is associated with AdverseOutcomepoor outcome , occurs more frequently in black women , and may contribute to racial disparity in survival .
15746676
HER2 and neu expression may guide clinical treatment of patients with Canceruterine serous papillary endometrial cancer and may have implications for the implementation of novel treatment strategies .
15758010
BACKGROUND : Epigenetic silencing of the MGMT ( O6-methylguanine-DNA methyltransferase ) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with Cancerglioblastoma who receive alkylating agents .
15758010
METHODS : We tested the relationship between MGMT silencing in the Cancertumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide .
15758010
Among patients whose Cancertumor contained a methylated MGMT promoter , a survival benefit was observed in patients treated with temozolomide and radiotherapy ; their median survival was 21.7 months ( 95 percent confidence interval , 17.4 to 30.4 ) , as compared with 15.3 months ( 95 percent confidence interval , 13.0 to 20.9 ) among those who were assigned to only radiotherapy ( P = 0.007 by the log-rank test ) .
15758010
CONCLUSIONS : Patients with Cancerglioblastoma containing a methylated MGMT promoter benefited from temozolomide , whereas those who did not have a methylated MGMT promoter did not have such a benefit .
15790433
OBJECTIVE : The aim of this study was to understand the role of PIK3CA and PTEN on the resistance of Cancerhuman ovarian cancer cells to cisplatin induced apoptosis .
15790433
METHODS : CancerHuman ovarian cancer cell OVCAR-3 and cisplatin resistant subclone OVCAR-3 and CDDP cells were used for these studies .
15824158
The G protein G ( alpha ) s pathway is linked to proapoptotic signaling in Cancercancer cell lines .
15824158
To assess the role of the GNAS1 locus encoding G ( alpha ) s as a genetic factor for Diseasedisease progression of transitional cell carcinoma ( TCC ) of the bladder , we genotyped the synonymous T393C polymorphism in 254 patients with TCC ( minor allele frequency : 0.43 ) to examine a potential association between genotypes and disease progression .
15824158
To assess the role of the GNAS1 locus encoding G ( alpha ) s as a genetic factor for disease progression of Cancertransitional cell carcinoma ( TCC ) of the bladder , we genotyped the synonymous T393C polymorphism in 254 patients with TCC ( minor allele frequency : 0.43 ) to examine a potential association between genotypes and disease progression .
15824158
To assess the role of the GNAS1 locus encoding G ( alpha ) s as a genetic factor for disease progression of transitional cell carcinoma ( TCC ) of the bladder , we genotyped the synonymous T393C polymorphism in 254 patients with TCC ( minor allele frequency : 0.43 ) to examine a potential association between genotypes and Diseasedisease progression .
15824158
Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up , we could show that progression-free survival , metastasis-free survival , and Cancercancer specific survival was significantly increased in TT genotypes ( 56 % , 84 % , 82 % ) compared with CC genotypes ( 35 % , 53 % , 58 % ) .
15824158
Homozygous CC patients were at highest AdverseOutcomerisk for progression [ odds ratio ( OR ) , 1.94 ; P = 0.020 ] , metastasis ( OR , 3.49 ; P = 0.005 ) , and tumor related death ( OR , 2.49 ; P = 0.031 ) compared with TT genotypes .
15824158
Homozygous CC patients were at highest risk for progression [ odds ratio ( OR ) , 1.94 ; P = 0.020 ] , Cancermetastasis ( OR , 3.49 ; P = 0.005 ) , and tumor related death ( OR , 2.49 ; P = 0.031 ) compared with TT genotypes .
15824158
Homozygous CC patients were at highest risk for progression [ odds ratio ( OR ) , 1.94 ; P = 0.020 ] , metastasis ( OR , 3.49 ; P = 0.005 ) , and Cancertumor related death ( OR , 2.49 ; P = 0.031 ) compared with TT genotypes .
15824158
Heterozygous patients had an AdverseOutcomeintermediate risk compatible with a gene-dose effect .
15824158
Real-time PCR analysis of Cancerurothelial tumor tissue as well as adipose and heart tissue revealed that G ( alpha ) s mRNA expression was highest in TT genotypes , indicating a proapoptotic effect in these genotypes .
15824158
In conclusion , the GNAS1 T393C status associated with differential G ( alpha ) s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G ( alpha ) s in Cancerbladder cancer progression .
15900596
Growth factor receptor mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on Cancercancer cells .
15900596
We describe a pathway that involves AKT and PI3K to mediate chemoresistance in Cancergastric cancer patients .
15900596
CancerPrimary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000 .
15900596
Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 Cancergastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000 .
15900596
AKT was phosphorylated in 22 cases ( 28.9 % ) of Cancergastric cancer cases .
15900596
We found that the Cancergastric cancer patients who had higher AKT phosphorylation ( activated AKT ) seemed to have LOH of PTEN ( p = 0.0008 ) .
15900596
The results of our study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in Cancergastric cancer patients .
15900596
It also indicates that AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of Cancergastric cancer patients .
15911866
PURPOSE : This randomized , multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 ( HER2 ) Cancer-positive metastatic breast cancer ( MBC ) .
15911866
PATIENTS AND METHODS : Patients were randomly assigned to six cycles of docetaxel 100 mg/m2 every 3 weeks , with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until Diseasedisease progression .
15911866
Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate ( 61 % v 34 % ; P = .0002 ) , overall survival ( median , 31.2 v 22.7 months ; P = .0325 ) , time to Diseasedisease progression ( median , 11.7 v 6.1 months ; P = .0001 ) , time to treatment failure ( median , 9.8 v 5.3 months ; P = .0001 ) , and duration of response ( median , 11.7 v 5.7 months ; P = .009 ) .
15911866
Grade 3 to 4 Diseaseneutropenia was seen more commonly with the combination ( 32 % ) than with docetaxel alone ( 22 % ) , and there was a slightly higher incidence of febrile neutropenia in the combination arm ( 23 % v 17 % ) .
15911866
Grade 3 to 4 neutropenia was seen more commonly with the combination ( 32 % ) than with docetaxel alone ( 22 % ) , and there was a slightly higher incidence of Diseasefebrile neutropenia in the combination arm ( 23 % v 17 % ) .
15911866
Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of Diseasedisease progression , while being treated with an investigational anthracycline for 4 months .
15911866
CONCLUSION : Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2 positive MBC in terms of overall survival , response rate , response duration , time to progression , and time to treatment failure , with Diseaselittle additional toxicity .
15922892
AIM : To investigate the role of coding region mutation and promoter hypermethylation of TP53 in Canceradrenocortical cancer formation .
15922892
METHODS : Twenty Cancersporadic adrenocortical cancers ( ACCs ) and five normal adrenal tissue samples were available for analysis .
15922892
Four of 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter and 3 of 4 died of Diseasedisease within 12 months of surgical resection .
15928335
PURPOSE : CancerGastrointestinal stromal tumors ( GISTs ) commonly harbor oncogenic mutations of the KIT tyrosine kinase , which is a target for the kinase inhibitor imatinib .
15928335
However , our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these Cancertumors .
15930265
Imatinib , a Bcr-Abl tyrosine kinase inhibitor , is a highly effective therapy for patients with Cancerchronic myelogenous leukemia ( CML ) .
15930265
Despite durable responses in most chronic phase patients , relapses have been observed and are much more prevalent in patients with Diseaseadvanced disease .
15932632
BACKGROUND : Biallelic von Hippel-Lindau ( VHL ) gene defects , a rate limiting event in the carcinogenesis , occur in approximately 75 % of Cancersporadic clear-cell Renal Cell Carcinoma ( RCC ) .
15932632
METHODS : Cases were identified within the Netherlands cohort study on diet and Cancercancer , which includes 120,852 men and women .
15932632
After 11.3 years of follow-up , 337 incident cases with histologically confirmed Cancerepithelial cancers were identified .
15932632
The Cancermean tumor size was 72.7 mm for mutated tumors compared to 65.3 mm for wildtype tumors ( p = 0.06 ) .
15932632
The mean tumor size was 72.7 mm for mutated Cancertumors compared to 65.3 mm for wildtype tumors ( p = 0.06 ) .
15932632
The mean tumor size was 72.7 mm for mutated tumors compared to 65.3 mm for Cancerwildtype tumors ( p = 0.06 ) .
15932632
In other histological types , we observed 8 mutations in 7 out of 48 patients ( 15 % ) , 1 mutation in 1 of 6 Canceroncocytoma , 3 mutations in 2 of 7 chromophobe RCC , 2 mutations in 2 of 30 papillary RCC , no mutations in 1 collecting duct carcinoma and 2 mutations in 2 of 4 unclassified RCC .
15932632
In other histological types , we observed 8 mutations in 7 out of 48 patients ( 15 % ) , 1 mutation in 1 of 6 oncocytoma , 3 mutations in 2 of 7 chromophobe RCC , 2 mutations in 2 of 30 papillary RCC , no mutations in 1 collecting Cancerduct carcinoma and 2 mutations in 2 of 4 unclassified RCC .
15951308
The pathogenesis of Canceracute myeloid leukemia ( AML ) involves the cooperation of mutations promoting proliferation and survival and those impairing differentiation .
15951308
RAS mutation did not influence clinical outcome ( overall and disease-free survival , complete remission , relapse rate ) either for the entire cohort or within AdverseOutcomecytogenetic risk groups .
15961768
Taking a perspective on available evidence that emphasizes relevance to Diseasehuman disease , cyclin D1 is solidly established as an oncogene with an important pathogenetic role in breast cancer and other human tumors .
15961768
Taking a perspective on available evidence that emphasizes relevance to human disease , cyclin D1 is solidly established as an oncogene with an important pathogenetic role in Cancerbreast cancer and other human tumors .
15961768
Taking a perspective on available evidence that emphasizes relevance to human disease , cyclin D1 is solidly established as an oncogene with an important pathogenetic role in breast cancer and Cancerother human tumors .
15961768
Although therapeutic exploitation of the role of cyclin D1 as a molecular driver of Cancerbreast cancer carries great promise , it is also suggested that direct targeting of the cyclin D1 gene or gene products may prove more successful than approaches that rely on arguably incomplete knowledge of the oncogenic mechanisms of cyclin D1 .
16033819
PURPOSE : Signaling via the G protein Galpha s pathway is linked to proapoptotic processes in Cancercancer cell lines .
16033819
We have recently shown an association between the GNAS1 T393C polymorphism and Diseasedisease progression in patients with bladder cancer with homozygous TT genotypes displaying increased transcription of Galpha s and a more favorable clinical course compared with C-allele carriers .
16033819
We have recently shown an association between the GNAS1 T393C polymorphism and disease progression in patients with Cancerbladder cancer with homozygous TT genotypes displaying increased transcription of Galpha s and a more favorable clinical course compared with C-allele carriers .
16033819
EXPERIMENTAL DESIGN : In the present study , 151 patients with Cancersporadic colorectal cancer were retrospectively genotyped to examine a potential association between T393C genotypes and survival .
16033819
Homozygous CC patients were at highest AdverseOutcomerisk for death ( hazard ratio , 12.1 ; P = 0.006 ) compared with TT genotypes .
16033819
Heterozygous patients had an AdverseOutcomeintermediate risk compatible with a gene-dose effect .
16033819
CONCLUSIONS : The results support the role of the T393C polymorphism as a marker for survival in patients with Cancercolorectal cancer stages I to II and in the identification of patients who may benefit from adjuvant chemotherapy .
16046528
Mutation of the nucleophosmin ( NPM ) gene has been reported as the most frequent mutation in Canceracute myeloid leukemia ( AML ) , especially in the presence of a normal karyotype .
16051734
To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with Canceracute myeloid leukemia ( AML ) and normal cytogenetics , sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group ( AMLSG ) .
16076867
Nucleophosmin ( NPM1 ) exon-12 gene mutations are the hallmark of a Cancerlarge acute myelogenous leukemia ( AML ) subgroup with normal karyotype , but their prognostic value in this AML subset has not yet been determined .
16081687
Activating mutations in tyrosine kinases have been identified in hematopoietic and Cancernonhematopoietic malignancies .
16081687
Recently , we and others identified a single recurrent somatic activating mutation ( JAK2V617F ) in the Janus kinase 2 ( JAK2 ) tyrosine kinase in the Diseasemyeloproliferative disorders ( MPDs ) polycythemia vera , essential thrombocythemia , and myeloid metaplasia with myelofibrosis .
16081687
Recently , we and others identified a single recurrent somatic activating mutation ( JAK2V617F ) in the Janus kinase 2 ( JAK2 ) tyrosine kinase in the myeloproliferative disorders ( MPDs ) Diseasepolycythemia vera , essential thrombocythemia , and myeloid metaplasia with myelofibrosis .
16081687
Recently , we and others identified a single recurrent somatic activating mutation ( JAK2V617F ) in the Janus kinase 2 ( JAK2 ) tyrosine kinase in the myeloproliferative disorders ( MPDs ) polycythemia vera , Diseaseessential thrombocythemia , and myeloid metaplasia with myelofibrosis .
16081687
We used direct sequence analysis to determine if the JAK2V617F mutation was present in Canceracute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
16081687
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , Cancerchronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
16081687
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CancerCMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
16081687
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , Diseasemyelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
16081687
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , CancerB-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
16081687
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and Cancerchronic lymphocytic leukemia ( CLL ) .
16081687
We did not identify the DiseaseJAK2V617F disease allele in B-lineage ALL ( n = 83 ) , T-cell ALL ( n = 93 ) , or CLL ( n = 45 ) .
16081687
These data indicate that the JAK2V617F allele is present in acute and Cancerchronic myeloid malignancies but not in lymphoid malignancies .
16081687
These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in Cancerlymphoid malignancies .
16088935
Linkage analysis suggests that mutations in the BRCA1 and BRCA2 genes are responsible for Cancercancer predisposition in more than 80 % of the families with high incidence of breast and ovarian cancer .
16088935
Linkage analysis suggests that mutations in the BRCA1 and BRCA2 genes are responsible for cancer predisposition in more than 80 % of the families with high incidence of breast and Cancerovarian cancer .
16088935
Here we report the identification of two different de novo Alu element insertions within the BRCA1/2 coding sequences in three out of the 50 families in which we found a Cancercancer predisposing mutation , suggesting that this type of mutation is much more common than suggested by their occurrence in mutation databases .
16088935
Finally , in contrast to the Diseasedisease causing Alu insertions reported to date , the transposon identified in the BRCA1 gene does not belong to a " young " AluY but to an AluS subfamily , indicating that some of these " old " Alu elements , which are supposed to be non functional fossil relics , are still able to retrotranspose in vivo .
16236737
BACKGROUND : Trastuzumab , a recombinant monoclonal antibody against HER2 , has clinical activity in Canceradvanced breast cancer that overexpresses HER2 .
16236737
We investigated its efficacy and safety after excision of Cancerearly-stage breast cancer and completion of chemotherapy .
16236737
METHODS : This international , multicenter , randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2 positive and either node negative or Cancernode positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy .
16236737
At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of Cancerbreast cancer , contralateral breast cancer , second nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group .
16236737
At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of breast cancer , Cancercontralateral breast cancer , second nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group .
16236737
At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of breast cancer , contralateral breast cancer , Diseasesecond nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group .
16236737
CONCLUSIONS : One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with CancerHER2 positive breast cancer .
16243825
PURPOSE : BRCA2 , FANCC , and FANCG gene mutations are present in a subset of Cancerpancreatic cancer .
16243825
Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of Cancerpancreatic cancer patients based on the genetic profile of the tumor .
16243825
Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the Cancertumor .
16243825
EXPERIMENTAL DESIGN : Two retrovirally complemented Cancerpancreatic cancer cell lines having defects in the Fanconi anemia pathway , PL11 ( FANCC mutated ) and Hs766T ( FANCG mutated ) , as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia and BRCA2 pathway , were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents .
16243825
EXPERIMENTAL DESIGN : Two retrovirally complemented pancreatic cancer cell lines having defects in the DiseaseFanconi anemia pathway , PL11 ( FANCC mutated ) and Hs766T ( FANCG mutated ) , as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia and BRCA2 pathway , were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents .
16243825
EXPERIMENTAL DESIGN : Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway , PL11 ( FANCC mutated ) and Hs766T ( FANCG mutated ) , as well as Cancerseveral parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia and BRCA2 pathway , were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents .
16243825
EXPERIMENTAL DESIGN : Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway , PL11 ( FANCC mutated ) and Hs766T ( FANCG mutated ) , as well as several parental pancreatic cancer cell lines with or without mutations in the DiseaseFanconi anemia and BRCA2 pathway , were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents .
16243825
CancerFanconi anemia defective cancer cells were hypersensitive to the cross linking agents mitomycin C ( MMC ) , cisplatin , chlorambucil , and melphalan but not to 5-fluorouracil , gemcitabine , doxorubicin , etoposide , vinblastine , or paclitaxel .
16243825
CONCLUSIONS : MMC or other cross linking agents as a clinical therapy for Cancerpancreatic cancer patients with tumors harboring defects in the Fanconi anemia and BRCA2 pathway should be specifically investigated .
16243825
CONCLUSIONS : MMC or other cross linking agents as a clinical therapy for pancreatic cancer patients with Cancertumors harboring defects in the Fanconi anemia and BRCA2 pathway should be specifically investigated .
16243825
CONCLUSIONS : MMC or other cross linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the DiseaseFanconi anemia and BRCA2 pathway should be specifically investigated .
16254181
Recurrent chromosomal rearrangements have not been well characterized in Cancercommon carcinomas .
16254181
Two ETS transcription factors , ERG and ETV1 , were identified as outliers in Cancerprostate cancer .
16254181
We identified recurrent gene fusions of the 5 ' untranslated region of TMPRSS2 to ERG or ETV1 in Cancerprostate cancer tissues with outlier expression .
16254181
By using fluorescence in situ hybridization , we demonstrated that 23 of 29 Cancerprostate cancer samples harbor rearrangements in ERG or ETV1 .
16254181
Cell line experiments suggest that the androgen responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in Cancerprostate cancer .
16254181
These results have implications in the development of Cancercarcinomas and the molecular diagnosis and treatment of prostate cancer .
16254181
These results have implications in the development of carcinomas and the molecular diagnosis and treatment of Cancerprostate cancer .
16258512
CancerEwing sarcoma and primitive neuroectodermal tumor ( EWS and PNET ) is a diagnostically challenging malignant round cell tumor with signature translocations involving the EWS gene .
16258512
Ewing sarcoma and Cancerprimitive neuroectodermal tumor ( EWS and PNET ) is a diagnostically challenging malignant round cell tumor with signature translocations involving the EWS gene .
16258512
Ewing sarcoma and primitive neuroectodermal tumor ( EWS and PNET ) is a diagnostically Cancerchallenging malignant round cell tumor with signature translocations involving the EWS gene .
16258512
Therefore , we have compared RT-PCR with FISH using ' home brew ' fusion probes for CancerEwing sarcoma ( EWS )-FLI1 and a commercial EWS break apart probe set in 67 archival round cell tumors , including 27 EWS and PNETs .
16258512
Therefore , we have compared RT-PCR with FISH using ' home brew ' fusion probes for Ewing sarcoma ( EWS )-FLI1 and a commercial EWS break apart probe set in 67 Cancerarchival round cell tumors , including 27 EWS and PNETs .
16258512
Nonetheless , Cancercomplex round cell tumors often benefit from molecular testing with multiple methods .
16282176
BACKGROUND : The epidermal growth factor receptor ( EGFR ) is frequently amplified , overexpressed , or mutated in Cancerglioblastomas , but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors .
16282176
The mechanism of responsiveness of Cancerglioblastomas to these inhibitors is unknown .
16282176
METHODS : We sequenced kinase domains in the EGFR and human EGFR type 2 ( Her2 and neu ) genes and analyzed the expression of EGFR , EGFR deletion mutant variant III ( EGFRvIII ) , and the tumor-suppressor protein PTEN in Cancerrecurrent malignant gliomas from patients who had received EGFR kinase inhibitors .
16282176
RESULTS : Of 49 patients with Cancerrecurrent malignant glioma who were treated with EGFR kinase inhibitors , 9 had tumor shrinkage of at least 25 percent .
16282176
RESULTS : Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors , 9 had Cancertumor shrinkage of at least 25 percent .
16282176
No mutations in EGFR or Her2 and neu kinase domains were detected in the Cancertumors .
16282176
These findings were validated in 33 patients who received similar treatment for Cancerglioblastoma at a different institution ( P = 0.001 ; odds ratio , 40 ; 95 percent confidence interval , 3 to 468 ) .
16282176
In vitro , coexpression of EGFRvIII and PTEN sensitized Cancerglioblastoma cells to erlotinib .
16282176
CONCLUSIONS : Coexpression of EGFRvIII and PTEN by Cancerglioblastoma cells is associated with responsiveness to EGFR kinase inhibitors .
16309541
Head and Cancerneck squamous cell carcinoma ( HNSCC ) involves the upper aerodigestive tract and can destroy the structure and function of organs involved in voice , speech , taste , smell and hearing , as well as vital structures necessary for survival .
16309541
HNSCC has long been a treatment challenge because of the high rate of recurrences and of Diseaseadvanced disease at the time of diagnosis .
16309541
Molecular identification of tissue biomarkers in diagnostic biopsy specimens may not only identify patients at AdverseOutcomerisk for developing HNSCC but may also select patients that may benefit from more aggressive treatment modalities .
16341243
Inhibitors of the kinase mammalian target of rapamycin ( mTOR ) have shown sporadic activity in Cancercancer trials , leading to confusion about the appropriate clinical setting for their use .
16341243
Here we show that loss of the Von Hippel-Lindau tumor suppressor gene ( VHL ) sensitizes Cancerkidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models .
16341243
CancerVHL deficient tumors show increased uptake of the positron emission tomography ( PET ) tracer fluorodeoxyglucose ( FDG ) in an mTOR dependent manner .
16341243
Our findings provide preclinical rationale for prospective , biomarker driven clinical studies of mTOR inhibitors in Cancerkidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting .
16384925
Distinct forms of tyrosine kinase domain ( TKD ) , juxtamembrane domain , exon 8 , and internal tandem duplication ( ITD ) mutations of c-KIT , were observed in about 46 % of Cancercore binding factor leukemia ( CBFL ) patients .
16384925
In Canceracute myeloid leukemia ( AML ) with t ( 8 ; 21 ) , the presence of c-KIT TKD mutation at codon 816 ( TKD ( 816 ) ) was associated with a high white blood cell count at diagnosis ( median , 29.60 x 10 ( 9 )/L ) and a higher incidence ( 33 % ) of extramedullary leukemia ( EML ) during the course of the disease .
16384925
In acute myeloid leukemia ( AML ) with t ( 8 ; 21 ) , the presence of c-KIT TKD mutation at codon 816 ( TKD ( 816 ) ) was associated with a high white blood cell count at diagnosis ( median , 29.60 x 10 ( 9 )/L ) and a higher incidence ( 33 % ) of Cancerextramedullary leukemia ( EML ) during the course of the disease .
16384925
In acute myeloid leukemia ( AML ) with t ( 8 ; 21 ) , the presence of c-KIT TKD mutation at codon 816 ( TKD ( 816 ) ) was associated with a high white blood cell count at diagnosis ( median , 29.60 x 10 ( 9 )/L ) and a higher incidence ( 33 % ) of extramedullary leukemia ( EML ) during the course of the Diseasedisease .
16404430
Trastuzumab is the only HER2 and neu directed therapy to have received Food and Drug Administration approval for the treatment of patients with Cancermetastatic breast cancer .
16404430
The efficacy of trastuzumab depends on the HER2 and neu status of the Cancertumour and the patient 's prior treatment , but even when patients are selected on the basis of HER2 and neu gene amplification , the single-agent response rate ranges from 12 to 30 % and few patients respond to trastuzumab monotherapy .
16404430
CancerHuman breast cancer SKBR3 and drug resistant SKBR3/R cells were investigated .
16404430
PTEN activity might play an important and major role in its HER2/PI3K/Akt mediated antitumour effect , and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of Cancerbreast cancer .
16434492
We analyzed 2502 patients with Canceracute myeloid leukemia at diagnosis for NRAS mutations around the hot spots at codons 12 , 13 , and 61 and correlated the results to cytomorphology , cytogenetics , other molecular markers , and prognostic relevance of these mutations .
16454808
BACKGROUND : The aim of this study was to evaluate the relationship between the expression of basic fibroblast growth factor ( bFGF ) and fibroblast growth factor receptor-1 ( FGFR-1 ) in Cancercancer cells and fibroblasts at the invasive front of oral squamous cell carcinoma ( OSCC ) , and the pathologic and clinical characteristics .
16454808
BACKGROUND : The aim of this study was to evaluate the relationship between the expression of basic fibroblast growth factor ( bFGF ) and fibroblast growth factor receptor-1 ( FGFR-1 ) in cancer cells and fibroblasts at the invasive front of Canceroral squamous cell carcinoma ( OSCC ) , and the pathologic and clinical characteristics .
16454808
METHODS : Sections of 61 biopsy specimens of primary OSCC were immunostained to assess the expression of bFGF and FGFR-1 in Cancercancer cells and fibroblasts at the invasive front .
16454808
RESULTS : The bFGF and FGFR-1 expressions in the Cancercancer cells were evident in all specimens , whilst , in fibroblasts , they were detected in 41 ( 67 % ) of 61 specimens .
16454808
The prevalence of bFGF and FGFR-1 expressions in cases with Cancerlymph node metastasis was significantly higher ( P < 0.05 ) than in cases without metastasis .
16454808
The prevalence of bFGF and FGFR-1 expressions in cases with lymph node metastasis was significantly higher ( P < 0.05 ) than in cases without Cancermetastasis .
16455956
Mutations of the nucleophosmin ( NPM1 ) gene have recently been described in patients with Canceracute myeloid leukemia ( AML ) .
16467086
In vitro Cancercancer cell line studies revealed a link between the Galphas protein and proapoptotic processes .
16467086
We have recently shown that TT genotypes of the GNAS1 T393C polymorphism display increased transcription of Galphas and a more favorable clinical course in bladder and Cancercolorectal cancer patients compared both with TC or CC genotypes .
16467086
EXPERIMENTAL DESIGN : In the present study , 150 patients with Cancerclear cell renal cell carcinoma surgically treated by nephrectomy with curative intent were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome .
16467086
RESULTS : The C-allele frequency in the Cancerrenal cell carcinoma patient group was 0.51 , which is not significantly different from that of a healthy blood donor group .
16467086
Kaplan-Meier curves for Cancertumor progression , development of metastasis , and tumor related death showed a significant association of the T393C polymorphism with outcome ( 5-year cancer specific survival rates : TT , 91 % ; TC , 81 % ; CC , 69 % ; P = 0.015 ) .
16467086
Kaplan-Meier curves for tumor progression , development of Cancermetastasis , and tumor related death showed a significant association of the T393C polymorphism with outcome ( 5-year cancer specific survival rates : TT , 91 % ; TC , 81 % ; CC , 69 % ; P = 0.015 ) .
16467086
Kaplan-Meier curves for tumor progression , development of metastasis , and Cancertumor related death showed a significant association of the T393C polymorphism with outcome ( 5-year cancer specific survival rates : TT , 91 % ; TC , 81 % ; CC , 69 % ; P = 0.015 ) .
16467086
Kaplan-Meier curves for tumor progression , development of metastasis , and tumor related death showed a significant association of the T393C polymorphism with outcome ( Cancer5-year cancer specific survival rates : TT , 91 % ; TC , 81 % ; CC , 69 % ; P = 0.015 ) .
16467086
Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in Cancerclear cell renal cell carcinoma .
16467086
Homozygous CC patients were at highest AdverseOutcomerisk for progression ( hazard ratio , 2.48 ; P = 0.009 ) or tumor related death ( hazard ratio , 3.15 ; P = 0.018 ) compared with T-allele carriers .
16467086
Homozygous CC patients were at highest risk for progression ( hazard ratio , 2.48 ; P = 0.009 ) or Cancertumor related death ( hazard ratio , 3.15 ; P = 0.018 ) compared with T-allele carriers .
16467086
CONCLUSION : Our results show that besides Cancertumor stage , lymph node status , and tumor grade , the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker .
16467086
CONCLUSION : Our results show that besides tumor stage , lymph node status , and Cancertumor grade , the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker .
16467086
CONCLUSION : Our results show that besides tumor stage , lymph node status , and tumor grade , the GNAS1 T393C status is a novel independent host factor for Diseasedisease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker .
16467086
CONCLUSION : Our results show that besides tumor stage , lymph node status , and tumor grade , the GNAS1 T393C status is a novel independent host factor for disease progression in patients with Cancerclear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker .
16467086
CONCLUSION : Our results show that besides tumor stage , lymph node status , and tumor grade , the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a Cancergeneral prognostic tumor marker .
16467099
We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in Cancerovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values .
16467099
EXPERIMENTAL DESIGN : Fifty-three patients were included in the study ; 28 of them had been relapse-free for at least 1 year and 25 had Diseaseprogressive disease or relapsed within 12 months .
16467099
CONCLUSIONS : The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in Cancerovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy .
16487996
BACKGROUND : CancerHigh-grade endometrial stromal sarcoma ( HGES ) is an aggressive disease with dismal prognosis .
16487996
BACKGROUND : High-grade endometrial stromal sarcoma ( HGES ) is an Diseaseaggressive disease with dismal prognosis .
16487996
No other treatment has proved to be useful in the case of Diseasenon resectable diseases .
16487996
Two years after surgical intervention , she is currently free of the Diseasedisease .
16489069
To investigate the clinical value of somatic TP53 mutations in Cancerbreast cancer , we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing .
16489069
To investigate the clinical value of somatic TP53 mutations in breast cancer , we assembled clinical and molecular data on 1,794 women with Cancerprimary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing .
16489069
To investigate the clinical value of somatic TP53 mutations in breast cancer , we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose Cancertumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing .
16489069
TP53 mutations were more frequent in Cancertumors of ductal and medullar types , aggressive phenotype ( high grade , large size , node positive cases , and low hormone receptor content ) and in women < 60 years old .
16489069
TP53 mutations within exons 5 to 8 conferred an AdverseOutcomeelevated risk of breast cancer specific death of 2.27 ( relative risk > 10 years ; P < 0.0001 ) compared with patients with no such mutation .
16489069
TP53 mutations within exons 5 to 8 conferred an elevated risk of Cancerbreast cancer specific death of 2.27 ( relative risk > 10 years ; P < 0.0001 ) compared with patients with no such mutation .
16489069
TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer specific death of 2.27 ( AdverseOutcomerelative risk > 10 years ; P < 0.0001 ) compared with patients with no such mutation .
16489069
The prognostic value of TP53 mutation was independent of Cancertumor size , node status , and hormone receptor content , confirming and reconciling previous findings in smaller series .
16489069
These results , obtained on the largest series analyzed thus far , show that TP53 mutations identified by gene sequencing have an independent prognostic value in Cancerbreast cancer and could have potential uses in clinical practice .
16497822
BACKGROUND : Most women with oestrogen receptor ( ER ) Cancerpositive primary breast cancer receive adjuvant tamoxifen after surgery .
16497822
The measurement of Cancertumour biomarkers should allow better selection of patients for such treatment or for therapies such as aromatase inhibitors .
16497822
PATIENTS AND METHODS : Histopathological blocks of Cancerprimary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature randomised clinical trials were retrieved .
16497822
Benefit from tamoxifen was seen in ER positive patients [ AdverseOutcomeRelative risk ( rr ) 0.77 , ci 0.63-0 .93 ] .
16497822
The data are consistent with CancerHER2 positive tumours being resistant to tamoxifen .
16497971
Oncogenic RAS expression occurs in up to 40 % of Cancermultiple myeloma ( MM ) cases and correlates with aggressive disease .
16497971
Oncogenic RAS expression occurs in up to 40 % of multiple myeloma ( MM ) cases and correlates with Diseaseaggressive disease .
16497971
Since activated RAS induces cyclooxygenase-2 ( cox-2 ) expression in Cancerother tumor models , we tested a role for cox-2 in mutant RAS containing MM cells .
16497971
Furthermore , in 3 primary marrow specimens , which contained MM cells expressing mutated RAS , 15 % to 40 % of Cancertumor cells were positive for cox-2 expression by immunohistochemistry .
16541434
BACKGROUND : Loss of heterozygosity ( LOH ) on chromosomes 1p and 19q has been associated with chemosensitivity and improved prognosis in patients with Canceroligodendrogliomas .
16541434
Recent studies demonstrated that temozolomide ( TMZ ) , an oral alkylating agent , has efficacy in the treatment of patients with progressive , Cancerlow-grade oligodendroglioma ( LGO ) .
16541434
Clinical and MRI data were used to evaluate outcomes , and Kaplan-Meier estimates were used to assess the median time to Cancertumor progression ( TTP ) .
16541434
MGMT protein expression was estimated semiquantitatively by immunohistochemistry using Cancerparaffin embedded tumor sections .
16541434
RESULTS : There were 28 patients who received treatment , and the median time from diagnosis to Cancertumor progression was 33.5 months .
16541434
The authors suggest the possible use of MGMT immunostaining as a surrogate marker for predicting Cancertumor chemosensitivity .
16551858
CancerGastrointestinal stromal tumors ( GIST ) are characterized by a strong KIT receptor activation most often resulting from KIT mutations .
16551858
In a smaller subgroup of Cancertumors without KIT mutations , analogous activating mutations are found in the platelet derived growth factor receptor alpha ( PDGFRalpha ) gene .
16551858
However , a subgroup of Cancertumors show a secondary progress under therapy with imatinib after initial response .
16551858
In the present study , we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which Cancertumor tissue was resected under treatment .
16551858
We examined one to seven Cancerdifferent tumor areas in 32 cases ( total of 104 samples ) and found up to four newly acquired KIT mutations in 14 patients ( 43.8 % ) .
16551858
Consistent with a secondary clonal evolution , the primary mutation was always detectable in all samples from each Cancertumor .
16618717
The anti-epidermal growth factor receptor ( anti-EGFR ) cetuximab has been proven to be efficient in Cancermetastatic colorectal cancer .
16618717
In this study , Cancertumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS , BRAF , and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization .
16618717
In this study , tumors from 30 Cancermetastatic colorectal cancer patients treated by cetuximab were screened for KRAS , BRAF , and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization .
16618717
A KRAS mutation was found in 13 Cancertumors ( 43 % ) and was significantly associated with the absence of response to cetuximab ( KRAS mutation in 0 % of the 11 responder patients versus 68.4 % of the 19 nonresponder patients ; P = 0.0003 ) .
16618717
The overall survival of patients without KRAS mutation in their Cancertumor was significantly higher compared with those patients with a mutated tumor ( P = 0.016 ; median , 16.3 versus 6.9 months ) .
16618717
The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a Cancermutated tumor ( P = 0.016 ; median , 16.3 versus 6.9 months ) .
16618717
An increased EGFR copy number was found in 3 patients ( 10 % ) and was significantly associated with an Cancerobjective tumor response to cetuximab ( P = 0.04 ) .
16624552
A recent randomized EORTC phase III trial , comparing two doses of imatinib in patients with Canceradvanced gastrointestinal stromal tumours ( GISTs ) , reported dose dependency for progression-free survival .
16624552
The current analysis of that study aimed to assess if Cancertumour mutational status correlates with clinical response to imatinib .
16624552
Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of Cancertumour genomic DNA .
16624552
The presence of exon 9 activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib , increasing the AdverseOutcomerelative risk of progression by 171 % ( P < 0.0001 ) and the relative risk of death by 190 % ( P < 0.0001 ) when compared with KIT exon 11 mutants .
16624552
The presence of exon 9 activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib , increasing the relative risk of progression by 171 % ( P < 0.0001 ) and the AdverseOutcomerelative risk of death by 190 % ( P < 0.0001 ) when compared with KIT exon 11 mutants .
16624552
Similarly , the AdverseOutcomerelative risk of progression was increased by 108 % ( P < 0.0001 ) and the relative risk of death by 76 % ( P = 0.028 ) in patients without detectable KIT or PDGFRA mutations .
16624552
Similarly , the relative risk of progression was increased by 108 % ( P < 0.0001 ) and the AdverseOutcomerelative risk of death by 76 % ( P = 0.028 ) in patients without detectable KIT or PDGFRA mutations .
16624552
In patients whose Cancertumours expressed an exon 9 KIT oncoprotein , treatment with the high-dose regimen resulted in a significantly superior progression-free survival ( P = 0.0013 ) , with a reduction of the relative risk of 61 % .
16624552
In patients whose tumours expressed an exon 9 KIT oncoprotein , treatment with the high-dose regimen resulted in a significantly superior progression-free survival ( P = 0.0013 ) , with a reduction of the AdverseOutcomerelative risk of 61 % .
16624552
We conclude that Cancertumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs .
16638875
PURPOSE : The majority of Cancergastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet derived growth factor receptor A ( PDGFRA ) , and respond to treatment with the tyrosine kinase inhibitor imatinib .
16638875
Some Cancertumors , however , show primary resistance to imatinib treatment , and most others become resistant during treatment .
16638875
EXPERIMENTAL DESIGN : CancerPrimary imatinib resistant tumor cells and cell lines expressing clinically identified imatinib resistant KIT-V654A , KIT-T670I , or PDGFRA D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays .
16638875
CONCLUSIONS : These studies suggest that SU11248 may be a useful therapeutic agent to treat Cancergastrointestinal stromal tumors harboring the imatinib resistant KIT-V654A or KIT T670I mutations , but it has no effect on the activity of the PDGFRA D842V mutant .
16690963
The prognosis for patients with Cancermantle cell lymphoma ( MCL ) is poor , and at present there is no truly effective therapy .
16707605
PURPOSE : Epidermal growth factor receptor ( EGFR ) mRNA expression and EGFR gene dosage by quantitative PCR in Cancertumor samples obtained from patients with gefitinib treated non small cell lung cancer were analyzed in order to determine the association with treatment outcome , clinical , and biological features [ EGFR copy number by fluorescent in situ hybridization ( FISH ) , EGFR tyrosine kinase mutations , and EGFR protein expression ] .
16707605
PURPOSE : Epidermal growth factor receptor ( EGFR ) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib treated Cancernon small cell lung cancer were analyzed in order to determine the association with treatment outcome , clinical , and biological features [ EGFR copy number by fluorescent in situ hybridization ( FISH ) , EGFR tyrosine kinase mutations , and EGFR protein expression ] .
16709929
V617F JAK2 mutation is a reliable molecular marker of Diseasepolycythemia vera ( PV ) , potentially useful to monitor the effect of treatments in this disease .
16709929
V617F JAK2 mutation is a reliable molecular marker of polycythemia vera ( PV ) , potentially useful to monitor the effect of treatments in this Diseasedisease .
16709929
The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that % V617F assessment using a quantitative method may provide the first tool to monitor Diseaseminimal residual disease in PV .
16730237
To understand the role of human epidermal growth factor receptor ( hEGFR ) kinase domain mutations in lung tumorigenesis and response to EGFR targeted therapies , we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in Cancerhuman lung cancer .
16730237
Both bitransgenic lines developed Cancerlung adenocarcinoma after sustained hEGFR mutant expression , confirming their oncogenic potential .
16730237
Maintenance of these Cancerlung tumors was dependent on continued expression of the EGFR mutants .
16730237
Treatment with small molecule inhibitors ( erlotinib or HKI-272 ) as well as prolonged treatment with a humanized anti-hEGFR antibody ( cetuximab ) led to Cancerdramatic tumor regression .
16730237
These data suggest that persistent EGFR signaling is required for Cancertumor maintenance in human lung adenocarcinomas expressing EGFR mutants .
16730237
These data suggest that persistent EGFR signaling is required for tumor maintenance in Cancerhuman lung adenocarcinomas expressing EGFR mutants .
16818618
CancerMutation specific cancer therapy has shown promising clinical efficacy .
16818618
In Cancernon-small-cell lung cancer ( NSCLC ) , the presence of mutations in the epidermal growth factor receptor ( EGFR ) tyrosine kinase correlates with clinical response to small-molecule tyrosine kinase inhibitors .
16818618
Thus , the subset of NSCLC patients with Cancertumors carrying the ERBB2 G776insV_G/C mutation may benefit from treatment with HKI-272 .
16818686
PURPOSE : Somatic mutations in the epidermal growth factor receptor ( EGFR ) have been detected in patients with Cancernon small cell lung cancer ( NSCLC ) and are associated with sensitivity to treatment with gefitinib or erlotinib .
16818686
EXPERIMENTAL DESIGN : CancerTumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations .
16875718
OBJECTIVES : The aim of the study was to assess whether the genetic polymorphisms were associated with the Cancertumor response in patients treated with platinum based neoadjuvant chemotherapy ( NAC ) for bulky cervical cancer .
16875718
OBJECTIVES : The aim of the study was to assess whether the genetic polymorphisms were associated with the tumor response in patients treated with platinum based neoadjuvant chemotherapy ( NAC ) for Cancerbulky cervical cancer .
16875718
METHODS : We retrospectively reviewed the clinical data and recruited paraffin embedded , formalin fixed tissues of 36 patients with Cancerbulky cervical carcinoma .
16875718
CONCLUSIONS : Genetic polymorphism of XRCC1 R399Q is associated with response to platinum based NAC in Cancerbulky cervical cancer , and MDR analysis documented association between gene gene interaction of XRCC1 R399Q and treatment response .
16906227
EGFR is frequently mutated and amplified in Cancerlung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib .
16906227
A secondary mutation , T790M , has been associated with acquired resistance but has not been shown to be sufficient to render EGFR mutant and amplified Cancerlung cancers resistant to EGFR inhibitors .
16906227
We created a model for studying acquired resistance to gefitinib by prolonged exposure of a Cancergefitinib sensitive lung carcinoma cell line ( H3255 ; EGFR mutated and amplified ) to gefitinib in vitro .
16906227
In Cancergefitinib sensitive lung cancer cells with EGFR mutations and amplifications , exogenous introduction of EGFR T790M effectively conferred resistance to gefitinib and continued ErbB-3/PI3K/Akt signaling when in cis to an activating mutation .
16906227
These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in Cancercancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib .
16943533
PURPOSE : High epidermal growth factor receptor ( EGFR ) gene copy number is associated with AdverseOutcomepoor prognosis in lung cancer , but such findings have not been reported for HNSCC .
16943533
PURPOSE : High epidermal growth factor receptor ( EGFR ) gene copy number is associated with poor prognosis in Cancerlung cancer , but such findings have not been reported for HNSCC .
16943533
PATIENTS AND METHODS : EGFR status was analyzed in 86 Cancertumor samples from 82 HNSCC patients by fluorescent in situ hybridization ( FISH ) to determine EGFR gene copy number , by polymerase chain reaction and direct sequencing for activating mutations , and by DNA microarray and immunohistochemistry for RNA and protein expression .
16943533
The FISH positive group did not differ from the FISH negative group with respect to age , sex , race , Cancertumor grade , subsites and stage , or EGFR expression by analyses of RNA or protein .
16943533
When microarray data were interrogated using the FISH results as a supervising parameter , ECop ( which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity ) had higher expression in CancerFISH positive tumors .
16954519
PURPOSE : CancerGastrointestinal stromal tumors ( GISTs ) commonly harbor oncogenic mutations of the KIT or platelet derived growth factor alpha ( PDGFRA ) kinases , which are targets for imatinib .
16954519
Specimens from pretreatment and/or Cancerimatinib resistant tumors were analyzed to identify molecular correlates of imatinib resistance .
16954519
CancerImatinib resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs .
16960151
Fusion genes derived from the platelet derived growth factor receptor beta ( PDGFRB ) or alpha ( PDGFRA ) play an important role in the pathogenesis of DiseaseBCR-ABL-negative chronic myeloproliferative disorders ( CMPDs ) .
17020971
PURPOSE : CancerB-cell chronic lymphocytic leukemia ( B-CLL ) is characterized by the accumulation of monoclonal mature B cells .
17020971
The G protein Galphas subunit has been linked to proapoptotic processes in Cancercancer cell lines .
17020971
The TT genotype of the GNAS1 T393C polymorphism is associated with increased Galphas transcript levels and a more favorable clinical course in Cancerdifferent solid cancers .
17020971
Regarding overall survival , CC genotypes ( median overall survival , 197 months ) were at highest AdverseOutcomerisk for death compared with T-alleles ( median overall survival , 310 months ) in both univariate ( HR , 4.8 ; P < 0.0001 ) and multivariable analysis ( HR , 5.6 ; P = 0.002 ) .
17020982
PURPOSE : CancerNon small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor ( EGFR ) are highly sensitive to EGFR specific tyrosine kinase inhibitors .
17020982
However , most patients who initially respond subsequently experience Diseasedisease progression while still on treatment .
17020982
EXPERIMENTAL DESIGN : We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in Cancertumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas .
17020982
EXPERIMENTAL DESIGN : We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with Canceradenocarcinomas .
17020982
We also looked for secondary KRAS gene mutations because Cancertumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors .
17020982
RESULTS : Seven of 14 Cancertumors had a secondary T790M mutation .
17020982
We detected no T790M mutations in pretreatment specimens from available five Cancertumors among these seven tumors .
17020982
We detected no T790M mutations in pretreatment specimens from available five tumors among these seven Cancertumors .
17020982
None of the Cancertumors had an acquired mutation in the KRAS gene .
17020982
CONCLUSIONS : A secondary T790M mutation of EGFR accounted for half the Cancertumors with acquired resistance to gefitinib in Japanese patients .
17024664
von Hippel-Lindau ( VHL ) Diseasedisease is a dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene .
17024664
von Hippel-Lindau ( VHL ) disease is a dominantly inherited Cancerfamilial cancer syndrome resulting from mutations in the VHL tumor suppressor gene .
17024664
von Hippel-Lindau ( VHL ) disease is a dominantly inherited Diseasefamilial cancer syndrome resulting from mutations in the VHL tumor suppressor gene .
17024664
DiseaseVHL disease displays marked variation in expression and the presence of pheochromocytoma has been linked to missense VHL mutations .
17024664
VHL disease displays marked variation in expression and the presence of Cancerpheochromocytoma has been linked to missense VHL mutations .
17024664
We analyzed genotype-phenotype correlations in 573 individuals with DiseaseVHL disease .
17024664
Routine clinical and radiological surveillance of VHL patients and at-risk relatives was associated with increased detection of retinal angiomatosis ( 73 vs. 59 % of cases ) and a reduction in age at diagnosis of Cancerrenal cell carcinoma ( RCC ) ( 44.0 +/-10.9 vs. 39.7 +/-10.3 years ) .
17024664
We confirmed the association of Cancerpheochromocytoma with missense mutations described previously , but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk .
17024664
We confirmed the association of pheochromocytoma with missense mutations described previously , but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a Cancerhigher pheochromocytoma risk .
17024664
We confirmed the association of pheochromocytoma with missense mutations described previously , but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma AdverseOutcomerisk .
17024664
Age at first manifestation of DiseaseVHL disease was significantly earlier ( P = 0.001 ) , and age related risks of retinal angiomas and RCC were higher ( P = 0.022 and P = 0.0008 , respectively ) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product ( pVHL ) .
17024664
Age at first manifestation of VHL disease was significantly earlier ( P = 0.001 ) , and age AdverseOutcomerelated risks of retinal angiomas and RCC were higher ( P = 0.022 and P = 0.0008 , respectively ) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product ( pVHL ) .
17024664
Age at first manifestation of VHL disease was significantly earlier ( P = 0.001 ) , and age related risks of Cancerretinal angiomas and RCC were higher ( P = 0.022 and P = 0.0008 , respectively ) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product ( pVHL ) .
17024664
These results extend genotype-phenotype-protein structure correlations in DiseaseVHL disease and provide a baseline for future chemoprevention studies in VHL disease .
17024664
These results extend genotype-phenotype-protein structure correlations in VHL disease and provide a baseline for future chemoprevention studies in DiseaseVHL disease .
17070615
PURPOSE : To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of Cancernon small cell lung cancer ( NSCLC ) , and to discuss the opportunities for targeted clinical intervention .
17070615
The protein is frequently overexpressed in a wide range of Cancercancers , sometimes coincident with CCND1 ( cyclin D1 ) gene amplification ( 5-20 % of tumours ) .
17070615
The protein is frequently overexpressed in a wide range of cancers , sometimes coincident with CCND1 ( cyclin D1 ) gene amplification ( 5-20 % of Cancertumours ) .
17070615
A low level of somatic mutations have been seen in Cancercertain tumours .
17070615
CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in Cancertumours and pre-invasive bronchial lesions , generally from one parental allele .
17070615
Genotype has been correlated with the AdverseOutcomerisk and/or severity of disease or drug response across a range of malignancies , including lung cancer .
17070615
Genotype has been correlated with the risk and/or severity of Diseasedisease or drug response across a range of malignancies , including lung cancer .
17070615
Genotype has been correlated with the risk and/or severity of disease or drug response across a range of Cancermalignancies , including lung cancer .
17070615
Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies , including Cancerlung cancer .
17070615
This understanding may open new avenues for Cancerlung cancer diagnosis , treatment and prevention .
17085664
PURPOSE : In patients whose Cancerlung adenocarcinomas harbor epidermal growth factor receptor ( EGFR ) tyrosine kinase domain mutations , acquired resistance to the tyrosine kinase inhibitors ( TKI ) gefitinib ( Iressa ) and erlotinib ( Tarceva ) has been associated with a second-site EGFR mutation , which leads to substitution of methionine for threonine at position 790 ( T790M ) .
17085664
EXPERIMENTAL DESIGN : CancerTumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses .
17085664
RESULTS : Eight of 16 patients ( 50 % observed rate ; 95 % confidence interval , 25-75 % ) had Cancertumor cells with second-site EGFR mutations .
17085664
Seven mutations were T790M and one was a novel D761Y mutation found in a Cancerbrain metastasis .
17088436
L-Asparaginase ( l-ASP ) , a bacterial enzyme used since the 1970s to treat Canceracute lymphoblastic leukemia , selectively starves cells that can not synthesize sufficient asparagine for their own needs .
17088436
Molecular profiling of the CancerNCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase ( ASNS ) expression and DNA copy number with sensitivity to l-ASP in the leukemia and ovarian cancer cell subsets .
17088436
Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase ( ASNS ) expression and DNA copy number with sensitivity to l-ASP in the Cancerleukemia and ovarian cancer cell subsets .
17088436
Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase ( ASNS ) expression and DNA copy number with sensitivity to l-ASP in the leukemia and Cancerovarian cancer cell subsets .
17088436
Tissue microarrays confirmed low ASNS expression in a subset of Cancerclinical ovarian cancers as well as other tumor types .
17088436
Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as Cancerother tumor types .
17088436
Overall , this pharmacogenomic and pharmacoproteomic study suggests the use of l-ASP for treatment of a subset of Cancerovarian cancers ( and perhaps other tumor types ) , with ASNS as a biomarker for patient selection .
17088436
Overall , this pharmacogenomic and pharmacoproteomic study suggests the use of l-ASP for treatment of a subset of ovarian cancers ( and perhaps Cancerother tumor types ) , with ASNS as a biomarker for patient selection .
17103226
Hypoxia inducible factor ( HIF )-1alpha is a transcription factor that supports the adaptation of Cancerhuman cancer cells to hypoxia and tumor growth and progression .
17103226
Hypoxia inducible factor ( HIF )-1alpha is a transcription factor that supports the adaptation of human cancer cells to hypoxia and Cancertumor growth and progression .
17103226
The overexpression of HIF-1alpha protein has been reported to be associated with a worse prognosis in Cancervarious cancers .
17103226
However , the expression of HIF-1alpha in Cancersoft-tissue sarcomas has not yet been characterized .
17103226
The expression of HIF-1alpha protein was immunohistochemically determined in 49 specimens of Cancersoft-tissue sarcomas including malignant fibrous histiocytoma ( 29 patients ) , synovial sarcoma ( 12 patients ) , leiomyosarcoma ( four patients ) , and malignant peripheral nerve sheath tumors ( four patients ) .
17103226
The expression of HIF-1alpha protein was immunohistochemically determined in 49 specimens of soft-tissue sarcomas including Cancermalignant fibrous histiocytoma ( 29 patients ) , synovial sarcoma ( 12 patients ) , leiomyosarcoma ( four patients ) , and malignant peripheral nerve sheath tumors ( four patients ) .
17103226
The expression of HIF-1alpha protein was immunohistochemically determined in 49 specimens of soft-tissue sarcomas including malignant fibrous histiocytoma ( 29 patients ) , Cancersynovial sarcoma ( 12 patients ) , leiomyosarcoma ( four patients ) , and malignant peripheral nerve sheath tumors ( four patients ) .
17103226
The expression of HIF-1alpha protein was immunohistochemically determined in 49 specimens of soft-tissue sarcomas including malignant fibrous histiocytoma ( 29 patients ) , synovial sarcoma ( 12 patients ) , Cancerleiomyosarcoma ( four patients ) , and malignant peripheral nerve sheath tumors ( four patients ) .
17103226
The expression of HIF-1alpha protein was immunohistochemically determined in 49 specimens of soft-tissue sarcomas including malignant fibrous histiocytoma ( 29 patients ) , synovial sarcoma ( 12 patients ) , leiomyosarcoma ( four patients ) , and Cancermalignant peripheral nerve sheath tumors ( four patients ) .
17103226
This is the first report that demonstrated an overexpression of HIF-1alpha protein to be an independent prognostic factor for Cancersoft-tissue sarcomas .
17186357
We have recently shown that genotypes of the single nucleotide polymorphism ( SNP ) T393C in the gene GNAS1 are associated with survival of patients suffering from bladder , renal cell and Cancercolorectal carcinoma .
17186357
In the present study , the genotypes of the T393C SNP were determined in 279 patients with Cancerinvasive breast carcinoma .
17186357
Comparing the genotypes with the overall survival as well as important clinico-pathological parameters showed that carriers of the T allele had a significantly less favourable course of the Diseasedisease when compared to carriers of the homozygous CC genotype .
17186357
Our results suggest that the GNAS1 T393C SNP is a novel genetic host factor for Diseasedisease progression in patients with invasive breast carcinoma .
17186357
Our results suggest that the GNAS1 T393C SNP is a novel genetic host factor for disease progression in patients with Cancerinvasive breast carcinoma .
17192538
BACKGROUND : Lapatinib , a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 ( HER2 , also referred to as HER2 and neu ) and epidermal growth factor receptor ( EGFR ) , is active in combination with capecitabine in women with CancerHER2 positive metastatic breast cancer that has progressed after trastuzumab based therapy .
17192538
METHODS : Women with HER2 positive , locally advanced or Cancermetastatic breast cancer that had progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab were randomly assigned to receive either combination therapy ( lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle ) or monotherapy ( capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle ) .
17192538
CONCLUSIONS : Lapatinib plus capecitabine is superior to capecitabine alone in women with CancerHER2 positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab .
17202311
PURPOSE : Somatic mutations of PIK3CA , which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase , have recently been shown to play an important role in the pathogenesis and progression of Cancerhuman breast cancers .
17202311
In this study , the frequency of PIK3CA mutations and their relationship with clinicopathologic and biological variables were investigated in CancerJapanese breast cancers .
17202311
EXPERIMENTAL DESIGN : Mutational analysis of PIK3CA was done in 188 Cancerprimary breast cancers of Japanese women .
17202311
Relationship of these mutations with various clinicopathologic variables [ histologic type , Cancertumor size , histologic grade , lymph node status , estrogen receptor ( ER )-alpha and progesterone receptor status , and prognosis ] , biological variables [ phospho-AKT ( pAKT ) and HER2 expression determined by immunohistochemistry ] , and p53 mutation status was studied .
17202311
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 Cancerinvasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 mucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
17202311
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas , 4 of 10 Cancerinvasive lobular carcinomas , 1 of 4 mucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
17202311
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 Cancermucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
17202311
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 mucinous carcinomas , 2 of 2 Cancersquamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
17202311
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 mucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 Cancerapocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
17202311
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 mucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 Cancernoninvasive ductal carcinomas .
17202311
PIK3CA mutated Cancertumors were found to be more likely to be ER-alpha positive ( P < 0.05 ) and pAKT positive ( P < 0.05 ) .
17202311
CONCLUSIONS : The frequency of PIK3CA mutations in CancerJapanese breast cancers is similar to that of Caucasian breast cancers .
17202311
CONCLUSIONS : The frequency of PIK3CA mutations in Japanese breast cancers is similar to that of CancerCaucasian breast cancers .
17224927
To identify predictive molecular markers for gemcitabine resistance , we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of Cancerpancreatic cancer cell lines .
17224927
Furthermore , the expression ratio significantly correlated with gemcitabine sensitivity in eight Cancerpancreatic cancer cell lines , whereas no single gene expression level correlated with the sensitivity .
17224927
These results suggest that the sensitivity of Cancerpancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism .
17224927
The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in Cancerpancreatic cancer cells , and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients .
17224927
The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells , and may be useful as a predictive marker for the efficacy of gemcitabine therapy in Cancerpancreatic cancer patients .
17356712
We have recently shown that TT genotypes of the single-nucleotide polymorphism T393C in the gene GNAS1 predict the clinical outcome of patients with Cancervarious carcinomas .
17356712
METHODS : Eighty-seven patients with Cancerintrahepatic cholangiocarcinoma ( ICC ) were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome .
17356712
Homozygous TT patients were at highest AdverseOutcomerisk for cancer related deaths ( hazard ratio = 2.74 ; 95 % confidence interval = 1.03-7 .28 ) compared with C-allele carriers .
17356712
Homozygous TT patients were at highest risk for Cancercancer related deaths ( hazard ratio = 2.74 ; 95 % confidence interval = 1.03-7 .28 ) compared with C-allele carriers .
17356712
Kaplan-Meier curves for Diseasedisease specific overall and local recurrence-free survival in a subgroup with R ( 0 )-resected ICC showed a significant association of T393 homozygosity with outcome , which was confirmed in multivariate Cox regression analysis .
17356712
CONCLUSIONS : GNAS1 T393C is a novel independent host factor for Diseasedisease progression in patients with ICC .
17356712
Our finding that TT homozygosity ( and not CC homozygosity ) was associated with unfavorable clinical outcome points to the complex and differing functional effects induced by GNAS1 T393C polymorphism in Cancervarious human carcinomas .
17372901
Activating mutations in either BRAF or NRAS are seen in a significant number of Cancermalignant melanomas , but their incidence appears to be dependent to ultraviolet light exposure .
17372901
Thus , BRAF mutations have the highest incidence in non chronic sun damaged ( CSD ) , and are uncommon in acral , mucosal and CancerCSD melanomas .
17372901
More recently , activating KIT mutations have been described in rare cases of Cancermetastatic melanoma , without further reference to their clinical phenotypes .
17372901
This finding is intriguing since KIT expression is downregulated in Cancermost melanomas progressing to more aggressive lesions .
17372901
In this study , we investigated a group of Canceranal melanomas for the presence of BRAF , NRAS , KIT and PDGFRA mutations .
17372901
The 3 KIT mutation carrying Cancertumors were strongly immunopositive for KIT protein .
17372901
No KIT mutations were identified in Cancertumors with less than 4+ KIT immunostaining .
17372901
NRAS mutation was identified in one Cancertumor .
17372901
No BRAF or PDGFRA mutations were identified in either KIT positive or Cancernegative anal melanomas .
17372901
These results suggest that a subset of Canceranal melanomas show activating KIT mutations , which are susceptible for therapy with specific kinase inhibitors .
17409929
BACKGROUND : We and other researchers have previously reported that Cancerpulmonary adenocarcinomas with epidermal growth factor receptor ( EGFR ) mutations are usually sensitive to gefitinib , an EGFR specific tyrosine kinase inhibitor , although this relationship is not complete .
17409929
METHODS : We studied 78 Cancerlung cancer patients who had recurrent disease after surgical resection and were treated with gefitinib .
17409929
METHODS : We studied 78 lung cancer patients who had Diseaserecurrent disease after surgical resection and were treated with gefitinib .
17409929
KRAS mutations were found only in Cancertumors without EGFR mutations , whereas PIK3CA mutation was found in tumors with EGFR mutation .
17409929
KRAS mutations were found only in tumors without EGFR mutations , whereas PIK3CA mutation was found in Cancertumors with EGFR mutation .
17409929
CancerTumor response was assessable in 52 tumors .
17409929
Tumor response was assessable in 52 Cancertumors .
17409929
None of the six Cancertumors with KRAS mutations responded to gefitinib treatment ; however , two tumors with PIK3CA mutations showed partial response .
17409929
None of the six tumors with KRAS mutations responded to gefitinib treatment ; however , two Cancertumors with PIK3CA mutations showed partial response .
17409929
In Cancertumors with EGFR mutations , survival was longer in those with high PIK3CA or PTEN expression than in those with low expression of these molecules .
17409929
CONCLUSIONS : An evaluation of the KRAS mutation , as well as PIK3CA and PTEN expression , might help identify Cancerlung cancer patients who are most suitable for gefitinib treatment .
17442989
PURPOSE : This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy ( RT ) in patients with inoperable newly diagnosed Cancerglioblastoma .
17442989
PATIENTS AND METHODS : Patients received temozolomide ( 150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days ; 7 days on/7 days off ) for up to four cycles before conventional RT ( 2-Gy fractions to a total of 60 Gy ) and for four cycles thereafter or until Diseasedisease progression .
17442989
The primary end point was Cancertumor response .
17442989
CancerTumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase ( MGMT ) expression .
17442989
Seven ( 24 % ) of 29 patients had a partial response , nine patients ( 31 % ) had Diseasestable disease , and 12 patients ( 41 % ) had progressive disease .
17442989
Seven ( 24 % ) of 29 patients had a partial response , nine patients ( 31 % ) had stable disease , and 12 patients ( 41 % ) had Diseaseprogressive disease .
17442989
The most common grade 3 and 4 Diseasetoxicities were thrombocytopenia ( 20 % ) and neutropenia ( 17 % ) .
17442989
The most common grade 3 and 4 toxicities were Diseasethrombocytopenia ( 20 % ) and neutropenia ( 17 % ) .
17442989
The most common grade 3 and 4 toxicities were thrombocytopenia ( 20 % ) and Diseaseneutropenia ( 17 % ) .
17463250
The epidermal growth factor receptor ( EGFR ) kinase inhibitors gefitinib and erlotinib are effective treatments for Cancerlung cancers with EGFR activating mutations , but these tumors invariably develop drug resistance .
17463250
The epidermal growth factor receptor ( EGFR ) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations , but these Cancertumors invariably develop drug resistance .
17463250
Here , we describe a Cancergefitinib sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene .
17463250
MET amplification was detected in 4 of 18 ( 22 % ) Cancerlung cancer specimens that had developed resistance to gefitinib or erlotinib .
17463250
Thus , we propose that MET amplification may promote drug resistance in other ERBB driven Cancercancers as well .
17470858
We compared the activity of panitumumab plus best supportive care ( BSC ) to that of BSC alone in patients with Cancermetastatic colorectal cancer who had progressed after standard chemotherapy .
17470858
PATIENTS AND METHODS : We randomly assigned 463 patients with 1 % or Cancermore EGFR tumor cell membrane staining , measurable disease , and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC ( n = 231 ) or BSC alone ( n = 232 ) .
17470858
PATIENTS AND METHODS : We randomly assigned 463 patients with 1 % or more EGFR tumor cell membrane staining , Diseasemeasurable disease , and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC ( n = 231 ) or BSC alone ( n = 232 ) .
17470858
PATIENTS AND METHODS : We randomly assigned 463 patients with 1 % or more EGFR tumor cell membrane staining , measurable disease , and radiologic documentation of Diseasedisease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC ( n = 231 ) or BSC alone ( n = 232 ) .
17470858
CancerTumor assessments by blinded central review were scheduled from week 8 until disease progression .
17470858
Tumor assessments by blinded central review were scheduled from week 8 until Diseasedisease progression .
17470858
DiseaseSkin toxicities , hypomagnesaemia , and diarrhea were the most common toxicities observed .
17470858
Skin toxicities , Diseasehypomagnesaemia , and diarrhea were the most common toxicities observed .
17470858
Skin toxicities , hypomagnesaemia , and diarrhea were the most Diseasecommon toxicities observed .
17470858
CONCLUSION : Panitumumab significantly improved PFS with Diseasemanageable toxicity in patients with chemorefractory colorectal cancer .
17470858
CONCLUSION : Panitumumab significantly improved PFS with manageable toxicity in patients with Cancerchemorefractory colorectal cancer .
17522398
BACKGROUND : Regular use of aspirin reduces the AdverseOutcomerisk of a colorectal neoplasm , but the mechanism by which aspirin affects carcinogenesis in the colon is not well understood .
17522398
We applied Cox regression to a competing-risks analysis to compare the effects of aspirin use on the AdverseOutcomerelative risk of colorectal cancer in relation to the expression of COX-2 in the tumor .
17522398
We applied Cox regression to a competing-risks analysis to compare the effects of aspirin use on the relative risk of Cancercolorectal cancer in relation to the expression of COX-2 in the tumor .
17522398
We applied Cox regression to a competing-risks analysis to compare the effects of aspirin use on the relative risk of colorectal cancer in relation to the expression of COX-2 in the Cancertumor .
17522398
RESULTS : During 2,446,431 person-years of follow-up of 82,911 women and 47,363 men , we found 636 Cancerincident colorectal cancers that were accessible for determination of COX-2 expression .
17522398
Of the Cancertumors , 423 ( 67 % ) had moderate or strong COX-2 expression .
17522398
Regular aspirin use conferred a significant reduction in the AdverseOutcomerisk of colorectal cancers that overexpressed COX-2 ( multivariate relative risk , 0.64 ; 95 % confidence interval [ CI ] , 0.52 to 0.78 ) , whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 ( multivariate relative risk , 0.96 ; 95 % CI , 0.73 to 1.26 ) .
17522398
Regular aspirin use conferred a significant reduction in the risk of Cancercolorectal cancers that overexpressed COX-2 ( multivariate relative risk , 0.64 ; 95 % confidence interval [ CI ] , 0.52 to 0.78 ) , whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 ( multivariate relative risk , 0.96 ; 95 % CI , 0.73 to 1.26 ) .
17522398
Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 ( multivariate AdverseOutcomerelative risk , 0.64 ; 95 % confidence interval [ CI ] , 0.52 to 0.78 ) , whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 ( multivariate relative risk , 0.96 ; 95 % CI , 0.73 to 1.26 ) .
17522398
Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 ( multivariate relative risk , 0.64 ; 95 % confidence interval [ CI ] , 0.52 to 0.78 ) , whereas regular aspirin use had no influence on Cancertumors with weak or absent expression of COX-2 ( multivariate relative risk , 0.96 ; 95 % CI , 0.73 to 1.26 ) .
17522398
Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 ( multivariate relative risk , 0.64 ; 95 % confidence interval [ CI ] , 0.52 to 0.78 ) , whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 ( multivariate AdverseOutcomerelative risk , 0.96 ; 95 % CI , 0.73 to 1.26 ) .
17522398
The age standardized incidence rate for Cancercancers that overexpressed COX-2 was 37 per 100,000 person-years among regular aspirin users , as compared with 56 per 100,000 person-years among those who did not use aspirin regularly ; in contrast , the rate for cancers with weak or absent COX-2 expression was 27 per 100,000 person-years among regular aspirin users , as compared with 28 per 100,000 person-years among nonregular aspirin users .
17522398
The age standardized incidence rate for cancers that overexpressed COX-2 was 37 per 100,000 person-years among regular aspirin users , as compared with 56 per 100,000 person-years among those who did not use aspirin regularly ; in contrast , the rate for Cancercancers with weak or absent COX-2 expression was 27 per 100,000 person-years among regular aspirin users , as compared with 28 per 100,000 person-years among nonregular aspirin users .
17522398
CONCLUSIONS : Regular use of aspirin appears to reduce the AdverseOutcomerisk of colorectal cancers that overexpress COX-2 but not the risk of colorectal cancers with weak or absent expression of COX-2 .
17522398
CONCLUSIONS : Regular use of aspirin appears to reduce the risk of Cancercolorectal cancers that overexpress COX-2 but not the risk of colorectal cancers with weak or absent expression of COX-2 .
17522398
CONCLUSIONS : Regular use of aspirin appears to reduce the risk of colorectal cancers that overexpress COX-2 but not the AdverseOutcomerisk of colorectal cancers with weak or absent expression of COX-2 .
17522398
CONCLUSIONS : Regular use of aspirin appears to reduce the risk of colorectal cancers that overexpress COX-2 but not the risk of Cancercolorectal cancers with weak or absent expression of COX-2 .
17538160
PURPOSE : Overexpression of epidermal growth factor receptor ( EGFR ) is common in head and Cancerneck squamous cell carcinoma ( HNSCC ) .
17538160
PATIENTS AND METHODS : The EGFR gene copy numbers in 134 CancerHNSCC tumors were determined using quantitative real-time polymerase chain reaction .
17538160
Mutation status of EGFR exons 18 , 19 , and 21 was determined in the CancerHNSCC tumors .
17538160
RESULTS : Aberrant EGFR copy numbers were found in 32 ( 24 % ) of 134 Cancertumors , including 22 ( 17 % ) with increased copy number and 10 ( 7 % ) with decreased copy number .
17538160
Patients whose Cancertumors had EGFR copy number alterations ( particularly patients with increased copy numbers ) had significantly poorer overall , cancer specific , and disease-free survivals compared with patients with normal copy numbers ( P < .0001 ) .
17538160
Patients whose tumors had EGFR copy number alterations ( particularly patients with increased copy numbers ) had significantly poorer overall , Cancercancer specific , and disease-free survivals compared with patients with normal copy numbers ( P < .0001 ) .
17538160
At 5 years after initial diagnosis , 20 ( 91 % ) of the 22 patients with increased copy numbers died of Diseasedisease compared with 30 ( 29 % ) of the 102 patients with normal copy number .
17538160
No mutations on EGFR exons 18 , 19 , and 21 were detected in any of the Cancertumors .
17590872
The PI3K-AKT pathway is activated in a variety of Cancerhuman cancers , resulting in disturbance of cell growth , proliferation and survival .
17590872
Among the factors affecting the pathway , the K-Ras mutation and PIK3CA mutation are the most common oncogenic alterations in Cancercolorectal cancer .
17590872
In this study , we aimed to examine the influence of PIK3CA mutation and K-Ras mutation on AKT activation , and to clarify whether PIK3CA mutation , K-Ras mutation and p-AKT expression may be used as parameters for predicting prognosis in Cancercolorectal cancer .
17590872
Tissue samples from 158 Cancercolorectal cancer patients who underwent surgical resection were examined .
17590872
As a result , PIK3CA mutation was significantly associated with shorter relapse-free survival ( RFS ) in stage II/III patients ( p = 0.0216 ) and Diseaseshorter disease specific survival in all patients ( p = 0.0357 ) .
17590872
This study revealed the prognostic value of PIK3CA mutation in Cancercolorectal cancer patients .
17625570
Improvement in the clinical outcome of Cancerlung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis .
17625570
Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule associated protein like 4 ( EML4 ) gene and the Canceranaplastic lymphoma kinase ( ALK ) gene in non-small-cell lung cancer ( NSCLC ) cells .
17625570
Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule associated protein like 4 ( EML4 ) gene and the anaplastic lymphoma kinase ( ALK ) gene in Cancernon-small-cell lung cancer ( NSCLC ) cells .
17625570
Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and Cancersubcutaneous tumours in nude mice .
17671205
Nutlin-3a is a recently discovered small-molecule antagonist of the p53 destabilizing protein murine double minute-2 ( MDM2 ) that induces cell cycle arrest and apoptosis in Cancercancer cells with functional p53 .
17671205
Here , we report that nutlin-3a induces cellular senescence in murine primary fibroblasts , oncogenically transformed fibroblasts , and Cancerfibrosarcoma cell lines .
17671205
Our current results suggest that senescence could be a major cellular outcome of Cancercancer therapy by antagonists of the p53-MDM2 interaction , such as nutlin-3a .
17700571
This study examines the clinical impact of PTEN genomic deletions using fluorescence in situ hybridisation ( FISH ) analysis of 107 Cancerprostate cancers , with follow-up information covering a period of up to 10 years .
17700571
Tissue microarray analysis using interphase FISH indicated that hemizygous PTEN losses were present in 42/107 ( 39 % ) of Cancerprostatic adenocarcinomas , with a homozygous PTEN deletion observed in 5/107 ( 5 % ) tumours .
17700571
Tissue microarray analysis using interphase FISH indicated that hemizygous PTEN losses were present in 42/107 ( 39 % ) of prostatic adenocarcinomas , with a homozygous PTEN deletion observed in 5/107 ( 5 % ) Cancertumours .
17700571
Kaplan-Meier survival analysis of PTEN genomic losses ( hemizygous and homozygous deletion vs not deleted ) identified subgroups with different prognosis based on their time to biochemical relapse after surgery , and demonstrated significant association between PTEN deletion and an earlier onset of Diseasedisease recurrence ( as determined by prostate specific antigen levels ) .
17700571
Furthermore , PTEN loss at the time of prostatectomy correlated with clinical parameters of Diseasemore advanced disease , such as extraprostatic extension and seminal vesicle invasion .
17700571
Collectively , our data indicates that haploinsufficiency or PTEN genomic loss is an indicator of Diseasemore advanced disease at surgery , and is predictive of a shorter time to biochemical recurrence of disease .
17700571
Collectively , our data indicates that haploinsufficiency or PTEN genomic loss is an indicator of more advanced disease at surgery , and is predictive of a shorter time to biochemical recurrence of Diseasedisease .
17891190
CancerMantle cell lymphoma ( MCL ) is a well defined lymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols .
17891190
Mantle cell lymphoma ( MCL ) is a well defined Cancerlymphoid malignancy characterized by a rapid clinical evolution and poor response to current therapeutic protocols .
17891190
Understanding these mechanisms and how they affect Cancertumour behaviour is providing the rationale for the identification of reliable predictors of clinical evolution and the design of innovative therapeutic strategies that could open new avenues for the treatment of patients with MCL .
17909070
Association studies in large series of Cancerbreast cancer patients can be used to identify single-nucleotide polymorphisms ( SNP ) contributing to breast cancer susceptibility .
17909070
Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms ( SNP ) contributing to Cancerbreast cancer susceptibility .
17909070
Previous studies have suggested associations between variants in TP53 ( R72P ) and MDM2 ( SNP309 ) and Cancercancer risk .
17909070
Previous studies have suggested associations between variants in TP53 ( R72P ) and MDM2 ( SNP309 ) and cancer AdverseOutcomerisk .
17909070
We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on Cancerbreast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium ( BCAC ) .
17909070
We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer AdverseOutcomerisk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium ( BCAC ) .
17909070
We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of Cancerbreast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium ( BCAC ) .
17909070
CancerBreast cancer risk was not found to be associated with the combined variant alleles [ odds ratio ( OR ) , 1.00 ; 95 % confidence interval ( 95 % CI ) , 0.81-1 .23 ] .
17909070
Breast cancer AdverseOutcomerisk was not found to be associated with the combined variant alleles [ odds ratio ( OR ) , 1.00 ; 95 % confidence interval ( 95 % CI ) , 0.81-1 .23 ] .
17909070
Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the Cancerbreast cancer patient series of the BCAC ( the German series ) , we were not able to confirm this effect in the pooled analysis .
17909070
Even so , carriers of both variant alleles did not have AdverseOutcomedifferent risk estimates for bilateral or estrogen receptor positive breast cancer .
17909070
Even so , carriers of both variant alleles did not have different risk estimates for bilateral or Cancerestrogen receptor positive breast cancer .
17909070
In conclusion , in this large collaborative study , we did not find an association of MDM2 SNP309 and TP53 R72P , separately or in interaction , with Cancerbreast cancer .
17936563
A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in Cancerbreast cancer identified only PTEN as a modulator of drug sensitivity .
17936563
Oncogenic mutants of PIK3CA ( activator of the same pathway and frequently mutated in Cancerbreast cancer ) also conferred resistance to trastuzumab in cell culture .
17936563
In a cohort of 55 Cancerbreast cancer patients , activation of the PI3K pathway , as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression , was associated with poor prognosis after trastuzumab therapy , and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone .
17936563
In a cohort of 55 breast cancer patients , activation of the PI3K pathway , as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression , was associated with AdverseOutcomepoor prognosis after trastuzumab therapy , and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone .
17936563
In a cohort of 55 breast cancer patients , activation of the PI3K pathway , as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression , was associated with poor prognosis after trastuzumab therapy , and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased AdverseOutcomerisk for progression compared to PTEN alone .
17940205
The prognostic relevance of FLT3 D835 and I836 mutations ( FLT3-TKD ) in cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) remains to be established .
17940205
After excluding patients with FLT3 internal tandem duplications , we compared treatment outcome of 16 de novo CN-AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 ( FLT3-WT ) , less than 60 years of age and similarly treated on CancerCancer and Leukemia Group B protocols .
17940205
After excluding patients with FLT3 internal tandem duplications , we compared treatment outcome of 16 de novo CN-AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 ( FLT3-WT ) , less than 60 years of age and similarly treated on Cancer and DiseaseLeukemia Group B protocols .
17957027
An internal tandem duplication in the fms like tyrosine kinase 3 gene ( FLT3 and ITD ) is associated with AdverseOutcomepoor prognosis in acute myeloid leukemia ( AML ) , but the impact of mutant level , size , and interaction with nucleophosmin 1 ( NPM1 ) mutations remains controversial .
17957027
An internal tandem duplication in the fms like tyrosine kinase 3 gene ( FLT3 and ITD ) is associated with poor prognosis in Canceracute myeloid leukemia ( AML ) , but the impact of mutant level , size , and interaction with nucleophosmin 1 ( NPM1 ) mutations remains controversial .
17957027
There was a highly significant trend for worsening in relapse AdverseOutcomerisk ( RR ) and overall survival ( OS ) with increasing FLT3 and ITD mutant level ( P < .001 for both ) , and even in the low level mutant group ( 1 %-24% of total FLT3 alleles ) , RR was significantly worse than in the FLT3 wild-type ( WT ) group ( P < .001 ) .
18003960
BACKGROUND : Cetuximab , an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor ( EGFR ) , has activity against Cancercolorectal cancers that express EGFR .
18003960
METHODS : From December 2003 to August 2005 , 572 patients who had Cancercolorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine , irinotecan , and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care ( 287 patients ) or best supportive care alone ( 285 patients ) .
18003960
RESULTS : In comparison with best supportive care alone , cetuximab treatment was associated with a significant improvement in overall survival ( hazard ratio for death , 0.77 ; 95 % confidence interval [ CI ] , 0.64 to 0.92 ; P = 0.005 ) and in progression-free survival ( hazard ratio for Diseasedisease progression or death , 0.68 ; 95 % CI , 0.57 to 0.80 ; P < 0.001 ) .
18003960
Partial responses occurred in 23 patients ( 8.0 % ) in the cetuximab group but in none in the group assigned to supportive care alone ( P < 0.001 ) ; the Diseasedisease was stable in an additional 31.4 % of patients assigned to cetuximab and in 10.9 % of patients assigned to supportive care alone ( P < 0.001 ) .
18003960
CONCLUSIONS : Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with Cancercolorectal cancer in whom other treatments have failed .
18073307
BACKGROUND : CancerMedullary thyroid carcinoma ( MTC ) is a well differentiated thyroid tumor that maintains the typical features of C cells .
18073307
BACKGROUND : Medullary thyroid carcinoma ( MTC ) is a well differentiated Cancerthyroid tumor that maintains the typical features of C cells .
18073307
RET mutation occurrence was more frequent in Cancerlarger tumors ( P = 0.03 ) , and in MTC with node and distant metastases ( P < 0.0001 and P = 0.02 , respectively ) , thus , a significant correlation was found with a more advanced stage at diagnosis ( P = 0.004 ) .
18073307
CONCLUSIONS : We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients , not only for the highest probability to have persistence of the Diseasedisease , but also for a lower survival rate in a long-term follow up .
18089725
A t ( 2 ; 5 ) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as Cancernucleophosmin-anaplastic lymphoma kinase ( NPM-ALK ) has been implicated in the pathogenesis of anaplastic large-cell lymphoma ( ALCL ) .
18089725
A t ( 2 ; 5 ) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase ( NPM-ALK ) has been implicated in the pathogenesis of Canceranaplastic large-cell lymphoma ( ALCL ) .
18089725
PF-2341066 potently inhibited cell proliferation , which was associated with G ( 1 )-S-phase cell cycle arrest and induction of apoptosis in ALK positive ALCL cells ( IC ( 50 ) values , approximately 30 nmol/L ) but not CancerALK negative lymphoma cells .
18089725
P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing CancerKarpas299 ALCL tumor xenografts resulted in dose dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration .
18089725
P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose dependent antitumor efficacy with complete regression of all Cancertumors at the 100 mg/kg/d dose within 15 days of initial compound administration .
18089725
A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in Cancertumor tissue .
18089823
Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of Cancernon small cell lung cancers .
18089823
In particular , Cancercancers with specific EGFR activating mutations seem to be the most sensitive to these agents .
18089823
However , despite their initial response , Cancersuch cancers almost invariably develop resistance .
18089823
In 50 % of Cancersuch cancers , a secondary EGFR mutation , T790M , has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity .
18089823
Additionally , PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib resistant oncogenic ERBB2 mutation identified in Cancerlung cancers .
18089823
These preclinical evaluations support further clinical development of PF00299804 for Cancercancers with mutations and/or amplifications of ERBB family members .
18202412
PURPOSE : Cetuximab is efficient in Canceradvanced colorectal cancer ( CRC ) .
18202412
PATIENTS AND METHODS : Eighty-nine metastatic CRC patients treated with cetuximab after treatment failure with irinotecan based chemotherapy were analyzed for KRAS mutation by allelic discrimination on Cancertumor DNA .
18202412
The association between KRAS mutations and Cancertumor response , skin toxicity , progression-free survival ( PFS ) and overall survival ( OS ) was analyzed .
18202412
The association between KRAS mutations and tumor response , Diseaseskin toxicity , progression-free survival ( PFS ) and overall survival ( OS ) was analyzed .
18202412
When we pooled these 89 patients with patients from our previous study , the multivariate analysis showed that KRAS status was an independent prognostic factor associated with OS and PFS , whereas Diseaseskin toxicity was only associated with OS .
18202412
In a combined analysis , median OS times of patients with two , one , or no favorable prognostic factors ( Diseasesevere skin toxicity and no KRAS mutation ) was of 15.6 , 10.7 , and 5.6 months , respectively .
18227510
CancerLung cancers caused by activating mutations in the epidermal growth factor receptor ( EGFR ) are initially responsive to small molecule tyrosine kinase inhibitors ( TKIs ) , but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation , T790M .
18230792
BACKGROUND : Internal tandem duplication ( ITD ) mutations in the juxtamembrane domain coding sequence of the Fms like tyrosine kinase 3 ( FLT3 ) gene have been identified in 30 % of Canceracute myeloid leukemia ( AML ) patients and are associated with a poor prognosis .
18230792
BACKGROUND : Internal tandem duplication ( ITD ) mutations in the juxtamembrane domain coding sequence of the Fms like tyrosine kinase 3 ( FLT3 ) gene have been identified in 30 % of acute myeloid leukemia ( AML ) patients and are associated with a AdverseOutcomepoor prognosis .
18230792
METHODS : The antileukemic activity of sorafenib was investigated in isogenic murine Ba/F3 AML cell lines that expressed mutant ( ITD , D835G , and D835Y ) or wild-type human FLT3 , in primary human AML cells , and in a Cancermouse leukemia xenograft model .
18230792
Effects of sorafenib on apoptosis and signaling in AML cell lines were investigated by flow cytometry and immunoblot analysis , respectively , and the in vivo effects were determined by monitoring the survival of Cancerleukemia xenograft bearing mice treated with sorafenib ( groups of 15 mice ) .
18230792
In a mouse model , sorafenib decreased the Cancerleukemia burden and prolonged survival ( median survival in the sorafenib treated group vs the vehicle treated group = 36.5 vs 16 days , difference = 20.5 days , 95 % confidence interval = 20.3 to 21.3 days ; P = .0018 ) .
18230792
Sorafenib reduced the percentage of Cancerleukemia blasts in the peripheral blood and the bone marrow of AML patients with FLT3-ITD ( median percentages before and after sorafenib : 81 % vs 7.5 % [ P = .016 ] and 75.5 % vs 34 % [ P = .05 ] , respectively ) but not in patients without this mutation .
18281551
PURPOSE : DiseasePeutz-Jeghers syndrome ( PJS ) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies .
18281551
PURPOSE : Peutz-Jeghers syndrome ( PJS ) is a Diseaseunique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies .
18281551
PURPOSE : Peutz-Jeghers syndrome ( PJS ) is a unique disorder characterized by the development of Cancerhamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies .
18281551
PURPOSE : Peutz-Jeghers syndrome ( PJS ) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased AdverseOutcomerisks for variety of malignancies .
18281551
PURPOSE : Peutz-Jeghers syndrome ( PJS ) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of Cancermalignancies .
18281551
We assessed the efficacy of rapamycin by measuring polyp sizes and Cancertumor burden .
18281551
RESULTS : We observed a significant decrease in Cancermean tumor burden ( Student 's t test , P = 0.023 ) as well as total tumor burden in rapamycin treated group compared with control group .
18281551
RESULTS : We observed a significant decrease in mean tumor burden ( Student 's t test , P = 0.023 ) as well as Cancertotal tumor burden in rapamycin treated group compared with control group .
18281551
Comparison of the polyp size observed in both rapamycin treated and control groups showed that rapamycin efficiently decreased the Cancertumor burden of large polyps ( > 8 mm ) .
18316791
PURPOSE : Panitumumab , a fully human antibody against the epidermal growth factor receptor ( EGFR ) , has activity in a subset of patients with Cancermetastatic colorectal cancer ( mCRC ) .
18316791
PATIENTS AND METHODS : KRAS mutations were detected using polymerase chain reaction on DNA from Cancertumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care ( BSC ) .
18316791
Consistent with longer exposure , more grade III Diseasetreatment related toxicities occurred in the WT KRAS group .
18316791
No significant differences in Diseasetoxicity were observed between the WT KRAS group and the overall population .
18316791
CONCLUSION : Panitumumab monotherapy efficacy in mCRC is confined to patients with CancerWT KRAS tumors .
18375819
Oncogenic BRAF and NRAS mutations are frequent in Cancermalignant melanoma .
18375819
Here , we explore the possible relationship between Cancertumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with metastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial .
18375819
Here , we explore the possible relationship between tumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with Cancermetastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial .
18375819
One patient with Diseasedisease stabilization for 49 months had a ( G13D ) NRAS mutation and ( WT ) BRAF .
18375819
A second patient who had Diseasestable disease for 15 months had a ( V600E ) BRAF mutation and ( WT ) NRAS .
18375819
These preliminary results suggest that BRAF and NRAS mutation status should be determined in prospective phase II studies of HSP90 inhibitors in Cancermelanoma .
18390968
PURPOSE : To assess the tolerability , pharmacokinetics ( PKs ) , and pharmacodynamics ( PDs ) of the mitogen activated protein kinase kinase ( MEK ) 1/2 inhibitor AZD6244 ( ARRY-142886 ) in patients with Canceradvanced cancer .
18390968
In part B , patients were stratified by Cancercancer type ( melanoma v other ) and randomly assigned to receive the MTD or 50 % MTD .
18390968
In part B , patients were stratified by cancer type ( Cancermelanoma v other ) and randomly assigned to receive the MTD or 50 % MTD .
18390968
MTD in part A was 200 mg bid , but this dose was discontinued in part B because of Diseasetoxicity .
18390968
Rash was the most frequent and dose limiting Diseasetoxicity .
18390968
CancerPaired tumor biopsies demonstrated reduced ERK phosphorylation ( geometric mean , 79 % ) .
18390968
Five of 20 patients demonstrated > or = 50 % inhibition of Ki-67 expression , and RAF or RAS mutations were detected in 10 of 26 Cancerassessable tumor samples .
18390968
Nine patients had Diseasestable disease ( SD ) for > or = 5 months , including two patients with SD for 19 ( thyroid cancer ) and 22 ( uveal melanoma plus renal cancer ) 28-day cycles .
18390968
Nine patients had stable disease ( SD ) for > or = 5 months , including two patients with SD for 19 ( Cancerthyroid cancer ) and 22 ( uveal melanoma plus renal cancer ) 28-day cycles .
18390968
Nine patients had stable disease ( SD ) for > or = 5 months , including two patients with SD for 19 ( thyroid cancer ) and 22 ( Canceruveal melanoma plus renal cancer ) 28-day cycles .
18390968
Nine patients had stable disease ( SD ) for > or = 5 months , including two patients with SD for 19 ( thyroid cancer ) and 22 ( uveal melanoma plus Cancerrenal cancer ) 28-day cycles .
18390968
Prolonged SD was seen in a variety of Canceradvanced cancers .
18394554
We report that TG101348 , a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM , shows therapeutic efficacy in a murine model of Diseasemyeloproliferative disease induced by the JAK2V617F mutation .
18394554
There were no Diseaseapparent toxicities and no effect on T cell number .
18394554
In vivo responses were correlated with surrogate endpoints , including reduction and elimination of DiseaseJAK2V617F disease burden assessed by quantitative genomic PCR , suppression of endogenous erythroid colony formation , and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5 .
18408761
Genetic alterations in the kinase domain of the epidermal growth factor receptor ( EGFR ) in Cancernon small cell lung cancer ( NSCLC ) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors .
18408761
Although first generation reversible , ATP-competitive inhibitors showed encouraging clinical responses in Cancerlung adenocarcinoma tumors harboring such EGFR mutations , almost all patients developed resistance to these inhibitors over time .
18408761
Consistent with this activity , BIBW2992 suppresses transformation in isogenic cell based assays , inhibits survival of Cancercancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models , with superior activity over erlotinib .
18408761
Consistent with this activity , BIBW2992 suppresses transformation in isogenic cell based assays , inhibits survival of cancer cell lines and induces Cancertumor regression in xenograft and transgenic lung cancer models , with superior activity over erlotinib .
18408761
Consistent with this activity , BIBW2992 suppresses transformation in isogenic cell based assays , inhibits survival of cancer cell lines and induces tumor regression in xenograft and Cancertransgenic lung cancer models , with superior activity over erlotinib .
18408761
These findings encourage further testing of BIBW2992 in Cancerlung cancer patients harboring EGFR or HER2 oncogenes .
18445659
We used the Cancerpaclitaxel resistant human small cell lung cancer subline PC-6 and TAX1-1 , selected from PC-6 cells by paclitaxel , to test whether MRP7 and ABCC10 ( ABCC10 ) confers paclitaxel resistance .
18445659
The expression levels of ABCC10 showed a significant inverse correlation with paclitaxel sensitivity ( r = 0.574 ; P < 0.05 ) in 17 Cancernon small cell lung cancer ( NSCLC ) cells unlike the expression levels of ABCB1 .
18450602
BACKGROUND : Mutations occur in several genes in cytogenetically Cancernormal acute myeloid leukemia ( AML ) cells : the nucleophosmin gene ( NPM1 ) , the fms related tyrosine kinase 3 gene ( FLT3 ) , the CCAAT and enhancer binding protein alpha gene ( CEPBA ) , the myeloid-lymphoid or mixed-lineage leukemia gene ( MLL ) , and the neuroblastoma RAS viral oncogene homolog ( NRAS ) .
18450602
BACKGROUND : Mutations occur in several genes in cytogenetically normal acute myeloid leukemia ( AML ) cells : the nucleophosmin gene ( NPM1 ) , the fms related tyrosine kinase 3 gene ( FLT3 ) , the CCAAT and enhancer binding protein alpha gene ( CEPBA ) , the myeloid-lymphoid or Cancermixed-lineage leukemia gene ( MLL ) , and the neuroblastoma RAS viral oncogene homolog ( NRAS ) .
18450602
BACKGROUND : Mutations occur in several genes in cytogenetically normal acute myeloid leukemia ( AML ) cells : the nucleophosmin gene ( NPM1 ) , the fms related tyrosine kinase 3 gene ( FLT3 ) , the CCAAT and enhancer binding protein alpha gene ( CEPBA ) , the myeloid-lymphoid or mixed-lineage leukemia gene ( MLL ) , and the Cancerneuroblastoma RAS viral oncogene homolog ( NRAS ) .
18450602
METHODS : We compared the mutational status of the NPM1 , FLT3 , CEBPA , MLL , and NRAS genes in Cancerleukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML .
18450602
Significant associations were found between the AdverseOutcomerisk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD ( hazard ratio , 0.44 ; 95 % confidence interval [ CI ] , 0.32 to 0.61 ) , the mutant CEBPA genotype ( hazard ratio , 0.48 ; 95 % CI , 0.30 to 0.75 ) , and the MLL-PTD genotype ( hazard ratio , 1.56 ; 95 % CI , 1.00 to 2.43 ) , as well as receipt of a transplant from an HLA matched related donor ( hazard ratio , 0.60 ; 95 % CI , 0.44 to 0.82 ) .
18450602
Significant associations were found between the risk of relapse or the AdverseOutcomerisk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD ( hazard ratio , 0.44 ; 95 % confidence interval [ CI ] , 0.32 to 0.61 ) , the mutant CEBPA genotype ( hazard ratio , 0.48 ; 95 % CI , 0.30 to 0.75 ) , and the MLL-PTD genotype ( hazard ratio , 1.56 ; 95 % CI , 1.00 to 2.43 ) , as well as receipt of a transplant from an HLA matched related donor ( hazard ratio , 0.60 ; 95 % CI , 0.44 to 0.82 ) .
18450602
Significant associations were found between the risk of relapse or the risk of death during complete remission and the Cancerleukemia genotype of mutant NPM1 without FLT3-ITD ( hazard ratio , 0.44 ; 95 % confidence interval [ CI ] , 0.32 to 0.61 ) , the mutant CEBPA genotype ( hazard ratio , 0.48 ; 95 % CI , 0.30 to 0.75 ) , and the MLL-PTD genotype ( hazard ratio , 1.56 ; 95 % CI , 1.00 to 2.43 ) , as well as receipt of a transplant from an HLA matched related donor ( hazard ratio , 0.60 ; 95 % CI , 0.44 to 0.82 ) .
18451166
Whereas these agents can elicit dramatic clinical responses in some settings , their activity is generally limited to a subset of treated patients whose Cancertumor cells harbor a specific genetic lesion .
18451166
We have established an automated platform for examining the sensitivity to various molecularly targeted inhibitors across a large panel of Cancerhuman tumor derived cell lines to identify additional genotype correlated responses that may be clinically relevant .
18451166
Among the inhibitors tested in a panel of 602 cell lines derived from a variety of Cancerhuman cancers , we found that a selective inhibitor of the anaplastic lymphoma kinase ( ALK ) potently suppressed growth of a small subset of tumor cells .
18451166
Among the inhibitors tested in a panel of 602 cell lines derived from a variety of human cancers , we found that a selective inhibitor of the Canceranaplastic lymphoma kinase ( ALK ) potently suppressed growth of a small subset of tumor cells .
18451166
Among the inhibitors tested in a panel of 602 cell lines derived from a variety of human cancers , we found that a selective inhibitor of the anaplastic lymphoma kinase ( ALK ) potently suppressed growth of a small subset of Cancertumor cells .
18451166
This subset included lines derived from Canceranaplastic large cell lymphomas , non-small-cell lung cancers , and neuroblastomas .
18451166
This subset included lines derived from anaplastic large cell lymphomas , Cancernon-small-cell lung cancers , and neuroblastomas .
18451166
This subset included lines derived from anaplastic large cell lymphomas , non-small-cell lung cancers , and Cancerneuroblastomas .
18451166
ALK is a receptor tyrosine kinase that was first identified as part of a protein fusion derived from a chromosomal translocation detected in the majority of Canceranaplastic large cell lymphoma patients , and has recently been implicated as an oncogene in a small fraction of non-small-cell lung cancers and neuroblastomas .
18451166
ALK is a receptor tyrosine kinase that was first identified as part of a protein fusion derived from a chromosomal translocation detected in the majority of anaplastic large cell lymphoma patients , and has recently been implicated as an oncogene in a small fraction of Cancernon-small-cell lung cancers and neuroblastomas .
18451166
ALK is a receptor tyrosine kinase that was first identified as part of a protein fusion derived from a chromosomal translocation detected in the majority of anaplastic large cell lymphoma patients , and has recently been implicated as an oncogene in a small fraction of non-small-cell lung cancers and Cancerneuroblastomas .
18451166
These findings suggest that a subset of Cancerlung cancers , lymphomas , and neuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition .
18451166
These findings suggest that a subset of lung cancers , Cancerlymphomas , and neuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition .
18451166
These findings suggest that a subset of lung cancers , lymphomas , and Cancerneuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition .
18464292
We attempted to describe , in a series of Cancerclear cell renal cell carcinoma ( RCC ) , the relationship between CAIX expression , VHL gene mutations , tumor characteristics and outcome .
18464292
We attempted to describe , in a series of clear cell renal cell carcinoma ( RCC ) , the relationship between CAIX expression , VHL gene mutations , Cancertumor characteristics and outcome .
18464292
Genomic DNA was extracted from Cancerfrozen tumor samples .
18464292
CancerTumors with VHL mutation showed higher CAIX expression than those without ( p = 0.02 ) .
18464292
Low CAIX expression and absence of VHL mutation were associated with a more Canceradvanced tumors e.g. , higher T stages and presence of metastases .
18464292
VHL mutation and high CAIX expression predicted longer progression-free survival ( p = 0.037 ) and Diseasedisease specific survival ( p = 0.001 ) , respectively .
18464292
In combination , they defined three prognostic groups ( p = 0.002 ) : ( i ) good prognosis , defined as VHL mutation and high CAIX ( 2-year survival : 86 % ) , ( ii ) intermediate prognosis with either VHL mutation or high CAIX ( 69 % ) , and ( iii ) AdverseOutcomepoor prognosis with no VHL mutation and low CAIX ( 45 % , median survival 18 months ) .
18478040
Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of Cancermyeloid malignancies ( familial platelet disorder with propensity to acute myeloid leukaemia , FPD and AML ) .
18478040
Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies ( Diseasefamilial platelet disorder with propensity to acute myeloid leukaemia , FPD and AML ) .
18478040
Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies ( familial platelet disorder with propensity to Diseaseacute myeloid leukaemia , FPD and AML ) .
18478040
We report on two novel germline RUNX1 mutations : ( 1 ) an out-of-frame 8 bp heterozygous deletion ( c. 442_449del ) in an FPD and AML pedigree and ( 2 ) a de novo 3.5 Mb deletion in the 21q22 .11.21 q22 .12 region encompassing the RUNX1 gene in a mentally retarded female patient with short stature and Diseasethrombocytopenia .
18478040
Mental retardation is one of the most Diseasecommon disorders and primary causes of thrombocytopenia are rare .
18478040
Mental retardation is one of the most common disorders and primary causes of Diseasethrombocytopenia are rare .
18509184
PURPOSE : To explore predictive factors for time to treatment failure ( TTF ) in Cancerchemotherapy-naive non-small-cell lung cancer ( NSCLC ) patients receiving gefitinib treatment .
18509184
CancerTumor assessments were performed every 2 months .
18509184
Responding or stable patients were treated until progression or Diseaseunacceptable toxicity .
18509184
Ninety patients had Cancertumor samples for biomarker tests .
18509184
In multivariate analysis , the presence of EGFR deletion exon 19 or L858R EGFR mutations in Canceradenocarcinoma patients predicted longer TTF .
18509184
CONCLUSION : In this prospective study , EGFR exon 19 deletion or L858R mutations in Canceradenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy .
18555254
OBJECTIVE : To study the effect of trastuzumab in patients with progressive or Cancerrecurrent metastatic endometrial carcinoma shown by immunohistochemistry to overexpress the HER2 and neu receptor .
18555254
METHODS : DiseaseDisease progression was examined in 2 patients who met the study criteria , had c-erbB2 gene amplification by fluorescence in situ hybridization , and were treated with trastuzumab following radiation treatment and/or salvage chemotherapy .
18555254
These patients with progressive or Diseaserecurrent metastatic disease experienced relief from their symptoms and prolonged survival with no significant toxicity observed .
18555254
These patients with progressive or recurrent metastatic disease experienced relief from their symptoms and prolonged survival with no Diseasesignificant toxicity observed .
18555254
CONCLUSION : Trastuzumab may be a viable therapeutic option as single agent or in combination with chemotherapy in patients with advanced , recurrent , and/or Cancermetastatic endometrial carcinomas overexpressing HER2 and neu .
18559874
PURPOSE : To analyze the prognostic impact of Wilms ' Cancertumor 1 ( WT1 ) gene mutations in cytogenetically normal acute myeloid leukemia ( CN-AML ) .
18559874
PURPOSE : To analyze the prognostic impact of Wilms ' tumor 1 ( WT1 ) gene mutations in cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) .
18559874
PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML , who were treated similarly on CancerCancer and Leukemia Group B ( CALGB ) protocols 9621 and 19808 , for WT1 mutations in exons 7 and 9 .
18559874
PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML , who were treated similarly on Cancer and DiseaseLeukemia Group B ( CALGB ) protocols 9621 and 19808 , for WT1 mutations in exons 7 and 9 .
18559874
In multivariable analyses , WT1 mutations independently predicted worse DFS ( P = .009 ; hazard ratio [ HR ] = 2.7 ) when controlling for CEBPA mutational status , ERG expression level , and FLT3-ITD and NPM1 molecular-risk group ( ie , FLT3-ITD ( negative )/NPM1 ( mutated ) as low AdverseOutcomerisk v FLT3-ITD ( positive ) and/or NPM1 ( wild-type ) as high risk ) .
18559874
In multivariable analyses , WT1 mutations independently predicted worse DFS ( P = .009 ; hazard ratio [ HR ] = 2.7 ) when controlling for CEBPA mutational status , ERG expression level , and FLT3-ITD and NPM1 molecular-risk group ( ie , FLT3-ITD ( negative )/NPM1 ( mutated ) as low risk v FLT3-ITD ( positive ) and/or NPM1 ( wild-type ) as AdverseOutcomehigh risk ) .
18559874
CONCLUSION : We report the first evidence that WT1 mutations independently predict extremely AdverseOutcomepoor outcome in intensively treated , younger patients with CN-AML .
18559874
Future trials should include testing for WT1 mutations as part of molecularly based AdverseOutcomerisk assessment and risk adapted treatment stratification of patients with CN-AML .
18559874
Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and AdverseOutcomerisk adapted treatment stratification of patients with CN-AML .
18591546
PURPOSE : To determine the clinical relevance of Wilms ' Cancertumor 1 ( WT1 ) gene mutations in acute myeloid leukemia ( AML ) with normal karyotype ( NK ) .
18591546
PURPOSE : To determine the clinical relevance of Wilms ' tumor 1 ( WT1 ) gene mutations in Canceracute myeloid leukemia ( AML ) with normal karyotype ( NK ) .
18591546
Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases ( complete remission rate , 79 % v 90 % , odds ratio [ OR ] = 3.02 ; 95 % CI , 1.17 to 7.82 ; P = .02 ) , a higher rate of Diseaseresistant disease ( 15 % v 4 % ; OR = 9.33 ; 95 % CI , 2.38 to 36.6 ; P = .001 ) , an increased cumulative incidence of relapse ( 67 % v 43 % , hazard ratio [ HR ] = 3.02 ; 95 % CI , 1.69 to 5.38 ; P = .0008 ) , with a reduction in both relapse-free survival ( 22 % v 44 % ; HR = 2.16 ; 95 % CI , 1.32 to 3.55 ; P = .005 ) and overall survival ( 26 % v 47 % ; HR = 1.91 ; 95 % CI , 1.23 to 2.95 ; P = .007 ) at 5 years .
18593892
The genome of a subset of Cancernon-small-cell lung cancers ( NSCLC ) harbors a small inversion within chromosome 2 that gives rise to a transforming fusion gene , EML4-ALK , which encodes an activated protein tyrosine kinase .
18593892
A Cancerlung cancer cell line expressing endogenous variant 3 of EML4-ALK underwent cell death on exposure to a specific inhibitor of ALK catalytic activity .
18593892
These data increase the frequency of CancerEML4-ALK-positive NSCLC tumors and bolster the clinical relevance of this oncogenic kinase .
18593940
CancerBreast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents .
18593940
Breast cancer is a Diseaseheterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents .
18593940
We have taken a functional genomics approach using a well characterized panel of Cancerbreast cancer cell lines to identify putative biomarkers of resistance to antimitotic agents such as paclitaxel and monomethyl-auristatin-E ( MMAE ) .
18593940
We also show that amplification of ABCC3 is present in Cancerprimary breast tumors and that it occurs predominantly in HER2 amplified and luminal tumors , and we report on development of a specific fluorescence in situ hybridization assay that may have utility as a predictive biomarker of taxane resistance in breast cancer .
18593940
We also show that amplification of ABCC3 is present in primary breast tumors and that it occurs predominantly in HER2 amplified and Cancerluminal tumors , and we report on development of a specific fluorescence in situ hybridization assay that may have utility as a predictive biomarker of taxane resistance in breast cancer .
18593940
We also show that amplification of ABCC3 is present in primary breast tumors and that it occurs predominantly in HER2 amplified and luminal tumors , and we report on development of a specific fluorescence in situ hybridization assay that may have utility as a predictive biomarker of taxane resistance in Cancerbreast cancer .
18594010
PURPOSE : The EML4-ALK fusion gene has been detected in approximately 7 % of CancerJapanese non small cell lung cancers ( NSCLC ) .
18594010
RESULTS : We detected four different variants , including two novel variants , of EML4-ALK using reverse transcription-PCR in 8 of 305 Cancertumors ( 3 % ) and 3 of 83 ( 3.6 % ) NSCLC cell lines .
18594010
All CancerEML4-ALK-containing tumors and cell lines were adenocarcinomas .
18594010
All EML4-ALK-containing tumors and cell lines were Canceradenocarcinomas .
18594010
ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose Cancertumors contain EML4-ALK .
18607592
CancerMalignant mesenchymal tumors consist of approximately 10 % of uterine tumors .
18607592
Malignant mesenchymal tumors consist of approximately 10 % of Canceruterine tumors .
18607592
The majority of Canceruterine sarcomas are leiomyosarcoma and endometrial stromal sarcoma ( ESS ) .
18607592
The majority of uterine sarcomas are Cancerleiomyosarcoma and endometrial stromal sarcoma ( ESS ) .
18607592
The majority of uterine sarcomas are leiomyosarcoma and Cancerendometrial stromal sarcoma ( ESS ) .
18607592
Imatinib mesylate is indicated in the management of Cancergastrointestinal stromal tumor and chronic myelogeneus leukemia .
18607592
Imatinib mesylate is indicated in the management of gastrointestinal stromal tumor and Cancerchronic myelogeneus leukemia .
18607592
FDG PET , a sensitive method for Cancertumor response evaluation on the basis of tumor metabolism changes , is useful for the evaluation of imatinib treatment in low-grade ESS .
18607592
FDG PET , a sensitive method for tumor response evaluation on the basis of Cancertumor metabolism changes , is useful for the evaluation of imatinib treatment in low-grade ESS .
18628482
PURPOSE : PALB2 is a recently identified Cancerbreast cancer susceptibility gene .
18628482
We have previously identified in the Finnish population a PALB2 c. 1592delT founder truncation mutation that is associated with an AdverseOutcomeincreased risk of breast cancer .
18628482
We have previously identified in the Finnish population a PALB2 c. 1592delT founder truncation mutation that is associated with an increased risk of Cancerbreast cancer .
18628482
In the present study , we wanted to assess in more detail the AdverseOutcomeincreased risk ( hazard ratio , HR ) and the age specific cumulative risk ( penetrance ) of c. 1592delT with regard to susceptibility to breast and other forms of cancer .
18628482
In the present study , we wanted to assess in more detail the increased risk ( hazard ratio , HR ) and the age specific AdverseOutcomecumulative risk ( penetrance ) of c. 1592delT with regard to susceptibility to breast and other forms of cancer .
18628482
In the present study , we wanted to assess in more detail the increased risk ( hazard ratio , HR ) and the age specific cumulative risk ( penetrance ) of c. 1592delT with regard to susceptibility to breast and other forms of Cancercancer .
18628482
EXPERIMENTAL DESIGN : Modified segregation analyses fitted under maximum likelihood theory were used to estimate age specific AdverseOutcomecumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history .
18628482
EXPERIMENTAL DESIGN : Modified segregation analyses fitted under maximum likelihood theory were used to estimate age specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of Cancerbreast cancer cases unselected for age at onset or family history .
18628482
RESULTS : We found a substantially increased AdverseOutcomerisk of breast cancer [ HR , 6.1 ; 95 % confidence interval ( 95 % CI ) , 2.2-17 .2 ; P = 0.01 ] equivalent to a 40 % ( 95 % CI , 17-77 ) breast cancer risk by age 70 years , comparable to that for carriers of mutations in BRCA2 .
18628482
RESULTS : We found a substantially increased risk of Cancerbreast cancer [ HR , 6.1 ; 95 % confidence interval ( 95 % CI ) , 2.2-17 .2 ; P = 0.01 ] equivalent to a 40 % ( 95 % CI , 17-77 ) breast cancer risk by age 70 years , comparable to that for carriers of mutations in BRCA2 .
18628482
RESULTS : We found a substantially increased risk of breast cancer [ HR , 6.1 ; 95 % confidence interval ( 95 % CI ) , 2.2-17 .2 ; P = 0.01 ] equivalent to a 40 % ( 95 % CI , 17-77 ) Cancerbreast cancer risk by age 70 years , comparable to that for carriers of mutations in BRCA2 .
18628482
RESULTS : We found a substantially increased risk of breast cancer [ HR , 6.1 ; 95 % confidence interval ( 95 % CI ) , 2.2-17 .2 ; P = 0.01 ] equivalent to a 40 % ( 95 % CI , 17-77 ) breast cancer AdverseOutcomerisk by age 70 years , comparable to that for carriers of mutations in BRCA2 .
18628482
We found marginal evidence ( P = 0.06 ) that the HR for Cancerbreast cancer decreased with age by 4.2 % per year ( 95 % CI , 0.2-8 .1 ) , from 7.5-fold at age 30 years to 2.0-fold at age 60 years .
18628482
CONCLUSIONS : Our results suggest that it may be appropriate to offer PALB2 c. 1592delT mutation testing to Finnish women with Cancerbreast cancer , especially those with an early age at onset or a family history of breast or related cancers , and to offer carriers the option of participation in extended disease surveillance programs .
18628482
CONCLUSIONS : Our results suggest that it may be appropriate to offer PALB2 c. 1592delT mutation testing to Finnish women with breast cancer , especially those with an early age at onset or a family history of breast or Cancerrelated cancers , and to offer carriers the option of participation in extended disease surveillance programs .
18628482
CONCLUSIONS : Our results suggest that it may be appropriate to offer PALB2 c. 1592delT mutation testing to Finnish women with breast cancer , especially those with an early age at onset or a family history of breast or related cancers , and to offer carriers the option of participation in Diseaseextended disease surveillance programs .
18632602
Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor ( EGFR ) signaling pathway have been implicated in the pathogenesis of Cancerhuman non-small-cell lung cancer ( NSCLC ) .
18632602
We performed mutational profiling of a large cohort of Cancerlung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis .
18632602
We have identified in 2 of 207 Cancerprimary lung tumors a somatic activating mutation in exon 2 of MEK1 ( i.e. , mitogen activated protein kinase kinase 1 or MAP2K1 ) that substitutes asparagine for lysine at amino acid 57 ( K57N ) in the nonkinase portion of the kinase .
18632602
Neither of these two Cancertumors harbored known mutations in other genes encoding components of the EGFR signaling pathway ( i.e. , EGFR , HER2 , KRAS , PIK3CA , and BRAF ) .
18632602
MEK1 mutants have not previously been reported in Cancerlung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma .
18632602
MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with Cancerlung adenocarcinoma .
18704422
PURPOSE : The aim of this study was to investigate the association of the thymidylate synthase ( TS ) and methylenetetrahydrofolate reductase ( MTHFR ) polymorphisms with the clinical outcomes of Cancergastric cancer patients treated with 5-FU-based adjuvant chemotherapy .
18704422
METHODS : One hundred and sixteen patients with Cancergastric cancer were treated with 5-FU-based adjuvant chemotherapy .
18704422
CONCLUSION : The polymorphisms of TS 3 '-UTR ins6 and del6 and MTHFR C677T appear to be potential prognostic factors in Cancergastric cancer patients treated with 5-FU-based adjuvant chemotherapy , which may allow identification of gastric cancer patients who will benefit from 5-FU chemotherapy .
18704422
CONCLUSION : The polymorphisms of TS 3 '-UTR ins6 and del6 and MTHFR C677T appear to be potential prognostic factors in gastric cancer patients treated with 5-FU-based adjuvant chemotherapy , which may allow identification of Cancergastric cancer patients who will benefit from 5-FU chemotherapy .
18725974
BACKGROUND : Dysregulated PI3K and Akt signaling occurs commonly in Cancerbreast cancers and is due to HER2 amplification , PI3K mutation or PTEN inactivation .
18725974
The objective of this study was to determine the role of Akt activation in Cancerbreast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy .
18725974
METHODOLOGY and PRINCIPAL FINDINGS : A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of Cancerbreast cancer cell lines characterized for genetic lesions that activate PI3K and Akt signaling : HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway .
18725974
A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that Cancertumors with mutational activation of Akt signaling were selectively dependent on the pathway .
18725974
Most importantly , the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of Cancerbreast cancer xenografts with PI3K mutation or HER2 amplification , including models of the latter selected for resistance to Herceptin .
18725974
Furthermore , chronic administration of the drug was well tolerated , causing only Diseasetransient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt .
18725974
Furthermore , chronic administration of the drug was well tolerated , causing only transient hyperglycemia without Diseasegross toxicity to the host despite the pleiotropic normal functions of Akt .
18725974
CONCLUSIONS and SIGNIFICANCE : These data demonstrate that Cancerbreast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling , and that effective inhibition of Akt in tumors is feasible and effective in vivo .
18725974
CONCLUSIONS and SIGNIFICANCE : These data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling , and that effective inhibition of Akt in Cancertumors is feasible and effective in vivo .
18725974
These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and Cancerother cancers that are addicted to the pathway including tumors with resistant to Herceptin .
18725974
These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including Cancertumors with resistant to Herceptin .
18757403
KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis , occurring in 10 % to 30 % and 26 % to 80 % of Cancerendometrial cancers , respectively .
18757403
Because we have recently shown activating mutations in fibroblast growth factor receptor 2 ( FGFR2 ) in 16 % of Cancerendometrioid endometrial cancers , we sought to determine the genetic context in which FGFR2 mutations occur .
18757403
Analysis of 116 Cancerprimary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive , whereas FGFR2 mutations were seen concomitantly with PTEN mutations .
18757403
Here , we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor , PD173074 , resulted in cell cycle arrest and induction of cell death in Cancerendometrial cancer cells with activating mutations in FGFR2 .
18757403
Together , these data suggest that inhibition of FGFR2 may be a viable therapeutic option in Cancerendometrial tumors possessing activating mutations in FGFR2 , despite the frequent abrogation of PTEN in this cancer type .
18757403
Together , these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2 , despite the frequent abrogation of PTEN in this Cancercancer type .
18765795
Gene expression profiling has been used to define 3 molecular subtypes of Cancerdiffuse large B-cell lymphoma ( DLBCL ) , termed germinal center B-cell-like ( GCB ) DLBCL , activated B-cell-like ( ABC ) DLBCL , and primary mediastinal B-cell lymphoma ( PMBL ) .
18765795
Gene expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma ( DLBCL ) , termed germinal center B-cell-like ( GCB ) DLBCL , activated B-cell-like ( ABC ) DLBCL , and Cancerprimary mediastinal B-cell lymphoma ( PMBL ) .
18765795
Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL , PMBL , or Cancermyeloma cell lines , strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL .
18765795
Together , these data provide genetic evidence that the DLBCL subtypes are Diseasedistinct diseases that use different oncogenic pathways .
18787170
The enzyme mTOR ( mammalian target of rapamycin ) is a major target for therapeutic intervention to treat Diseasemany human diseases , including cancer , but very little is known about the processes that control levels of mTOR protein .
18787170
The enzyme mTOR ( mammalian target of rapamycin ) is a major target for therapeutic intervention to treat many human diseases , including Cancercancer , but very little is known about the processes that control levels of mTOR protein .
18787170
CancerHuman breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN ( phosphatase and tensin homolog ) , which also activates mTOR .
18787170
Human breast cancer cell lines and Cancerprimary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN ( phosphatase and tensin homolog ) , which also activates mTOR .
18787170
CancerTumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment , which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway .
18787170
Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment , which suggests that loss of FBXW7 may be a biomarker for Cancerhuman cancers susceptible to treatment with inhibitors of the mTOR pathway .
18794081
PURPOSE : KRAS mutations are found in approximately 25 % of Cancerlung adenocarcinomas in Western countries and , as a group , have been strongly associated with cigarette smoking .
18794081
These mutations are predictive of AdverseOutcomepoor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib .
18794081
These mutations are predictive of poor prognosis in Diseaseresected disease as well as resistance to treatment with erlotinib or gefitinib .
18794081
EXPERIMENTAL DESIGN : We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with Cancerlung adenocarcinomas .
18794081
RESULTS : KRAS mutational analysis was done on 482 Cancerlung adenocarcinomas , 81 ( 17 % ) of which were obtained from patients who had never smoked cigarettes .
18794081
KRAS mutations were found in 15 % ( 12 of 81 ; 95 % confidence intervals , 8-24 % ) of Cancertumors from never smokers .
18794081
Similarly , 22 % ( 69 of 316 ; 95 % confidence intervals , 17-27 % ) of Cancertumors from former smokers , and 25 % ( 21 of 85 ; 95 % confidence intervals , 16-35 % ) of tumors from current smokers had KRAS mutations .
18794081
Similarly , 22 % ( 69 of 316 ; 95 % confidence intervals , 17-27 % ) of tumors from former smokers , and 25 % ( 21 of 85 ; 95 % confidence intervals , 16-35 % ) of Cancertumors from current smokers had KRAS mutations .
18794081
CONCLUSIONS : Based on our data , KRAS mutations are not rare among never smokers with Cancerlung adenocarcinoma and such patients have a distinct KRAS mutation profile .
18794081
The etiologic and biological heterogeneity of CancerKRAS mutant lung adenocarcinomas is worthy of further study .
18794099
PURPOSE : To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor ( EGFR ) gene copy number ( GCN ) by fluorescence in situ hybridization ( FISH ) for outcome prediction to cetuximab in Cancermetastatic colorectal cancer .
18794099
EXPERIMENTAL DESIGN : FISH analysis of 87 Cancermetastatic colorectal cancer patients treated with cetuximab was done , recording individual GCN per cell and using different samples per tumor .
18794099
EXPERIMENTAL DESIGN : FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done , recording individual GCN per cell and using different samples per Cancertumor .
18794099
Important heterogeneity of repeated measures of mean EGFR GCN was observed within Cancertumors ( intraclass correlation , 0.61 ; within-class SD , 0.40 ) , leading to potential misclassifications of FISH status in 7 of 18 ( 38.8 % ) patients if a cutoff point were used .
18818391
We reviewed patients with Cancerchronic myeloid leukemia and mutations after tyrosine kinase inhibitor ( TKI ) therapy .
18818391
The prognosis is dependent mostly on the Diseasedisease stage .
18829560
Phosphatidylinositol-3-kinase ( PI3K ) pathway deregulation is a common event in Cancerhuman cancer , either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of p110-alpha .
18829560
The PI3K pathway is , therefore , an attractive target for Cancercancer therapy .
18829560
NVP-BEZ235 inhibited the activation of the downstream effectors Akt , S6 ribosomal protein , and 4EBP1 in Cancerbreast cancer cells .
18829560
The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 Cancercancer cell lines of different origin and mutation status .
18829560
In Cancertrastuzumab resistant BT474 H1047R breast cancer xenografts , NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity .
18829560
In summary , NVP-BEZ235 inhibits the PI3K and mTOR axis and results in antiproliferative and antitumoral activity in Cancercancer cells with both wild-type and mutated p110-alpha .
18832571
Desmoid specimens ( 195 Cancertumors from 160 patients , 1985 to 2005 ) and control dermal scars were assembled into a clinical data linked tissue microarray .
18832571
Five-year recurrence-free survival was significantly poorer in 45F mutated desmoids ( 23 % , P < 0.0001 ) versus either 41A ( 57 % ) or Cancernonmutated tumors ( 65 % ) .
18832571
In conclusion , CTNNB1 mutations are highly common in Cancerdesmoid tumors .
18832571
Furthermore , patients harboring CTNNB1 ( 45F ) mutations are at AdverseOutcomeparticular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches .
18923525
CancerNeuroblastoma , an embryonal tumour of the peripheral sympathetic nervous system , accounts for approximately 15 % of all deaths due to childhood cancer .
18923525
Neuroblastoma , an Cancerembryonal tumour of the peripheral sympathetic nervous system , accounts for approximately 15 % of all deaths due to childhood cancer .
18923525
Neuroblastoma , an embryonal tumour of the peripheral sympathetic nervous system , accounts for approximately 15 % of all deaths due to Cancerchildhood cancer .
18923525
CancerHigh-risk neuroblastomas are rapidly progressive ; even with intensive myeloablative chemotherapy , relapse is common and almost uniformly fatal .
18923525
Here we report the detection of previously unknown mutations in the ALK gene , which encodes a receptor tyrosine kinase , in 8 % of Cancerprimary neuroblastomas .
18923525
The most frequent mutation , F1174L , was also identified in three Cancerdifferent neuroblastoma cell lines .
18923525
Furthermore , two Cancerhuman neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor .
18923525
Short hairpin RNA ( shRNA )-mediated knockdown of ALK expression in Cancerneuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation .
18923525
Thus , activating alleles of the ALK receptor tyrosine kinase are present in Cancerprimary neuroblastoma tumours and in established neuroblastoma cell lines , and confer sensitivity to ALK inhibition with small molecules , providing a molecular rationale for targeted therapy of this disease .
18923525
Thus , activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in Cancerestablished neuroblastoma cell lines , and confer sensitivity to ALK inhibition with small molecules , providing a molecular rationale for targeted therapy of this disease .
18923525
Thus , activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines , and confer sensitivity to ALK inhibition with small molecules , providing a molecular rationale for targeted therapy of this Diseasedisease .
18927303
PURPOSE : EML4-ALK is a fusion-type protein tyrosine kinase that is generated by inv ( 2 ) ( p21p23 ) in the genome of Cancernon small cell lung cancer ( NSCLC ) .
18927303
EXPERIMENTAL DESIGN : Primers were designed to detect all possible in-frame fusions of EML4 to exon 20 of ALK , and a single-tube multiplex RT-PCR assay was done with total RNA from 656 Cancersolid tumors of the lung ( n = 364 ) and 10 other organs .
18927303
RESULTS : From Cancerconsecutive lung adenocarcinoma cases ( n = 253 ) , we identified 11 specimens ( 4.35 % ) positive for fusion transcripts , 9 of which were positive for the previously identified variants 1 , 2 , and 3 .
18927303
No fusion transcripts were detected for other types of Cancerlung cancer ( n = 111 ) or for tumors from 10 other organs ( n = 292 ) .
18927303
No fusion transcripts were detected for other types of lung cancer ( n = 111 ) or for Cancertumors from 10 other organs ( n = 292 ) .
18927303
CONCLUSIONS : These data reinforce the importance of accurate diagnosis of CancerEML4-ALK-positive tumors for the optimization of treatment strategies .
18946061
BACKGROUND : Treatment with cetuximab , a monoclonal antibody directed against the epidermal growth factor receptor , improves overall and progression-free survival and preserves the quality of life in patients with Cancercolorectal cancer that has not responded to chemotherapy .
18946061
The mutation status of the K-ras gene in the Cancertumor may affect the response to cetuximab and have treatment independent prognostic value .
18946061
METHODS : We analyzed Cancertumor samples , obtained from 394 of 572 patients ( 68.9 % ) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone , to look for activating mutations in exon 2 of the K-ras gene .
18946061
METHODS : We analyzed tumor samples , obtained from 394 of 572 patients ( 68.9 % ) with Cancercolorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone , to look for activating mutations in exon 2 of the K-ras gene .
18946061
RESULTS : Of the Cancertumors evaluated for K-ras mutations , 42.3 % had at least one mutation in exon 2 of the gene .
18946061
In patients with Cancerwild-type K-ras tumors , treatment with cetuximab as compared with supportive care alone significantly improved overall survival ( median , 9.5 vs. 4.8 months ; hazard ratio for death , 0.55 ; 95 % confidence interval [ CI ] , 0.41 to 0.74 ; P < 0.001 ) and progression-free survival ( median , 3.7 months vs. 1.9 months ; hazard ratio for progression or death , 0.40 ; 95 % CI , 0.30 to 0.54 ; P < 0.001 ) .
18946061
Among patients with mutated CancerK-ras tumors , there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival ( hazard ratio , 0.98 ; P = 0.89 ) or progression-free survival ( hazard ratio , 0.99 ; P = 0.96 ) .
18946061
CONCLUSIONS : Patients with a Cancercolorectal tumor bearing mutated K-ras did not benefit from cetuximab , whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab .
18946061
CONCLUSIONS : Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab , whereas patients with a Cancertumor bearing wild-type K-ras did benefit from cetuximab .
18951446
Genetic testing of Cancercancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer .
18951446
Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict AdverseOutcomerisk of developing cancer .
18951446
Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing Cancercancer .
18951446
In this article we review the current state of sequence based genetic testing , describe other standardized reporting systems used in oncology , and propose a standardized classification system for application to sequence based results for Cancercancer predisposition genes .
18951446
Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the Diseasesyndrome .
18951446
We propose that panels of experts on each Diseasecancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines .
18951446
We propose that panels of experts on each Cancercancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines .
18951446
We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and Cancercancer management guidelines .
18951446
The international adoption of a standardized reporting system should improve the clinical utility of sequence based genetic tests to predict Cancercancer risk .
18951446
The international adoption of a standardized reporting system should improve the clinical utility of sequence based genetic tests to predict cancer AdverseOutcomerisk .
18955458
PURPOSE : CancerMost gastrointestinal stromal tumors ( GISTs ) harbor mutant KIT or platelet derived growth factor receptor alpha ( PDGFRA ) kinases , which are imatinib targets .
18955458
PATIENTS AND METHODS : CancerTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic , imatinib-resistant and intolerant GIST .
18955458
KIT and PDGFRA mutational status was determined for 78 patients by using Cancertumor specimens obtained before and after prior imatinib therapy .
18955458
RESULTS : Clinical benefit ( partial response or Diseasestable disease for > or = 6 months ) with sunitinib was observed for the three most common primary GIST genotypes : KIT exon 9 ( 58 % ) , KIT exon 11 ( 34 % ) , and wild-type KIT and PDGFRA ( 56 % ) .
19001320
PURPOSE Cetuximab or panitumumab are effective in 10 % to 20 Cancer% unselected metastatic colorectal cancer ( CRC ) patients .
19001320
PATIENTS AND METHODS We retrospectively analyzed Cancerobjective tumor responses , time to progression , overall survival ( OS ) , and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab treated metastatic CRC patients .
19001320
PATIENTS AND METHODS We retrospectively analyzed objective tumor responses , time to progression , overall survival ( OS ) , and the mutational status of KRAS and BRAF in 113 Cancertumors from cetuximab- or panitumumab treated metastatic CRC patients .
19029981
Furthermore , clinical trials with PI3K inhibitors have recently been initiated , and it is unknown if their efficacy will be restricted to specific , genetically defined Cancermalignancies .
19029981
In this study , we engineered a mouse model of Cancerlung adenocarcinomas initiated and maintained by expression of p110-alpha H1047R .
19029981
Treatment of these Cancertumors with NVP-BEZ235 , a dual pan-PI3K and mammalian target of rapamycin ( mTOR ) inhibitor in clinical development , led to marked tumor regression as shown by positron emission tomography computed tomography , magnetic resonance imaging and microscopic examination .
19029981
Treatment of these tumors with NVP-BEZ235 , a dual pan-PI3K and mammalian target of rapamycin ( mTOR ) inhibitor in clinical development , led to Cancermarked tumor regression as shown by positron emission tomography computed tomography , magnetic resonance imaging and microscopic examination .
19029981
In contrast , Cancermouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235 .
19029981
However , when NVP-BEZ235 was combined with a mitogen activated protein kinase kinase ( MEK ) inhibitor , ARRY-142886 , there was marked synergy in shrinking these CancerKras-mutant cancers .
19029981
These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in Cancercancers with PIK3CA mutations and , when combined with MEK inhibitors , may effectively treat KRAS mutated lung cancers .
19029981
These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and , when combined with MEK inhibitors , may effectively treat KRAS mutated Cancerlung cancers .
19035443
Recent studies showed KIT gene aberrations in a substantial number of Cancermelanomas on acral skin and mucosa , suggesting the therapeutic benefit of tyrosine kinase inhibitors , such as imatinib .
19035443
We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and Cancermucosal melanomas .
19035443
Immunohistochemistry revealed moderate or strong KIT protein expression in 13 ( 48 % ) Cancertumors .
19035443
Amplification of KIT was identified by real-time PCR in 4 Cancertumors , including one that had K642E .
19035443
Phosphorylation of KIT protein was detected in 2 Cancertumors harboring KIT mutations , as well as in one tumor with KIT gene amplification .
19035443
Phosphorylation of KIT protein was detected in 2 tumors harboring KIT mutations , as well as in one Cancertumor with KIT gene amplification .
19035443
Furthermore , 5 Cancertumors without detectable KIT gene aberrations showed phosphorylation of the KIT receptor .
19035443
Expression of stem cell factor ( SCF ) in Cancermelanoma cells as well as stromal cells suggests SCF and KIT autocrine and paracrine activation in these tumors .
19035443
Expression of stem cell factor ( SCF ) in melanoma cells as well as stromal cells suggests SCF and KIT autocrine and paracrine activation in these Cancertumors .
19035443
Finally , we found significant growth suppressive effects of sunitinib in two Canceracral melanoma cell lines ; one harboring the D820Y mutation and one showing SCF dependent KIT activation .
19035443
These results show pathological activation of KIT in a substantial number of Cancermetastatic tumors of acral and mucosal melanomas , and suggest a potential therapeutic benefit of sunitinib for these melanomas .
19035443
These results show pathological activation of KIT in a substantial number of metastatic tumors of acral and Cancermucosal melanomas , and suggest a potential therapeutic benefit of sunitinib for these melanomas .
19035443
These results show pathological activation of KIT in a substantial number of metastatic tumors of acral and mucosal melanomas , and suggest a potential therapeutic benefit of sunitinib for these Cancermelanomas .
19040416
The majority of Cancerlung adenocarcinomas express the lineage specific thyroid transcription factor-1 ( TTF-1 ) .
19040416
We recently reported that in a subset of Cancerlung adenocarcinomas the TTF-1 gene is amplified .
19040416
We studied 89 consecutive patients with Cancerlung adenocarcinomas treated by surgery at Brigham and Women 's Hospital between 1997 and 1999 and performed immunohistochemical analysis for TTF-1 expression and fluorescence in situ hybridization for TTF-1 amplification .
19040416
Patients with Canceradenocarcinomas with low or high TTF-1 expression had a significantly better outcome than those with absent TTF-1 expression ( median overall survival times of 72.4 , 77.8 and 30.5 months , respectively , P = 0.002 ) .
19040416
In contrast , patients with Canceradenocarcinomas with TTF-1 expression had a worse outcome if TTF-1 was amplified ( median overall survival time 39.5 versus 87.5 months ) .
19040416
In patients with Cancerlung adenocarcinoma , TTF-1 expression is a predictor of good outcome .
19047294
PURPOSE : The purpose of the study was to assess the contribution of age and Diseasedisease variables to the outcome of untreated patients with acute myeloid leukemia ( AML ) receiving varying intensive induction chemotherapy .
19047294
PURPOSE : The purpose of the study was to assess the contribution of age and disease variables to the outcome of untreated patients with Canceracute myeloid leukemia ( AML ) receiving varying intensive induction chemotherapy .
19047294
CONCLUSION : Under harmonized conditions , older and younger patients with AML show modest differences in their AdverseOutcomerisk profiles and equally no dose response to intensified chemotherapy .
19059939
BACKGROUND : In a previous randomized trial , AML HD98B , we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with Canceracute myeloid leukemia .
19059939
CONCLUSIONS : In elderly patients with Canceracute myeloid leukemia , NPM1 mutations are associated with achievement of complete remission , and the genotype ' mutant NPM1 without FLT3-ITD ' appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy ( ClinicalTrials.gov Identifier : NCT00151242 ) .
19118063
PURPOSE : Recent studies suggest that temozolomide has activity in Cancerneuroendocrine tumors .
19118063
Low levels of the DNA repair enzyme , O ( 6 )-methylguanine DNA methyltransferase ( MGMT ) , are associated with sensitivity to temozolomide in Cancerother tumor types .
19118063
We evaluated the prevalence of MGMT deficiency in Cancerneuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide based regimens .
19118063
EXPERIMENTAL DESIGN : The prevalence of MGMT deficiency , measured by immunohistochemistry , was assessed in 97 Cancerarchival neuroendocrine tumor specimens .
19118063
Rates of treatment response and survival were next evaluated in a cohort of 101 Cancerconsecutive neuroendocrine tumor patients who had received treatment with a temozolomide based regimen at one of three institutions .
19118063
MGMT expression was directly correlated with treatment response in 21 patients who had Canceravailable tumor tissue and response data .
19118063
RESULTS : In archival specimens , MGMT deficiency was observed in 19 of 37 ( 51 % ) Cancerpancreatic neuroendocrine tumors and 0 of 60 ( 0 % ) carcinoid tumors ( P < 0.0001 ) .
19118063
RESULTS : In archival specimens , MGMT deficiency was observed in 19 of 37 ( 51 % ) pancreatic neuroendocrine tumors and 0 of 60 ( 0 % ) Cancercarcinoid tumors ( P < 0.0001 ) .
19118063
In the clinical cohort , 18 of 53 ( 34 % ) patients with Cancerpancreatic neuroendocrine tumors but only 1 of 44 ( 2 % ) patients with carcinoid tumors ( P < 0.001 ) experienced a partial or complete response to temozolomide based therapy .
19118063
In the clinical cohort , 18 of 53 ( 34 % ) patients with pancreatic neuroendocrine tumors but only 1 of 44 ( 2 % ) patients with Cancercarcinoid tumors ( P < 0.001 ) experienced a partial or complete response to temozolomide based therapy .
19118063
Among 21 patients with Cancerevaluable tumor tissue who had also received treatment with temozolomide , 4 of 5 patients with MGMT deficient tumors ( all pancreatic neuroendocrine tumors ) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment ( P = 0.001 ) .
19118063
Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide , 4 of 5 patients with CancerMGMT deficient tumors ( all pancreatic neuroendocrine tumors ) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment ( P = 0.001 ) .
19118063
Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide , 4 of 5 patients with MGMT deficient tumors ( all Cancerpancreatic neuroendocrine tumors ) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment ( P = 0.001 ) .
19118063
Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide , 4 of 5 patients with MGMT deficient tumors ( all pancreatic neuroendocrine tumors ) and 0 of 16 patients with Cancertumors showing intact MGMT expression responded to treatment ( P = 0.001 ) .
19118063
CONCLUSIONS : MGMT deficiency , measured by immunohistochemistry , is more common in Cancerpancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide based therapy .
19118063
CONCLUSIONS : MGMT deficiency , measured by immunohistochemistry , is more common in pancreatic neuroendocrine tumors than in Cancercarcinoid tumors as is treatment response to temozolomide based therapy .
19118063
Absence of MGMT may explain the sensitivity of some Cancerpancreatic neuroendocrine tumors to treatment .
19122144
Mutations in the HER2 kinase domain have been identified in Cancerhuman clinical lung cancer specimens .
19122144
Here we demonstrate that inducible expression of the most common HER2 mutant ( HER2 ( YVMA ) ) in mouse lung epithelium causes Cancerinvasive adenosquamous carcinomas restricted to proximal and distal bronchioles .
19122144
Continuous expression of HER2 ( YVMA ) is essential for Cancertumor maintenance , suggesting a key role for HER2 in lung adenosquamous tumorigenesis .
19122144
Preclinical studies assessing the in vivo effect of erlotinib , trastuzumab , BIBW2992 , and/or rapamycin on HER2 ( YVMA ) transgenic mice or H1781 xenografts with documented Cancertumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage .
19122144
Preclinical studies assessing the in vivo effect of erlotinib , trastuzumab , BIBW2992 , and/or rapamycin on HER2 ( YVMA ) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing Cancersignificant tumor shrinkage .
19122144
Immunohistochemical analysis of Cancerlung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt and mTOR signaling axes , indicating inhibition of these pathways .
19122144
Based on these findings , clinical testing of the BIBW2992 and rapamycin combination in Cancernon small cell lung cancer patients with tumors expressing HER2 mutations is warranted .
19122144
Based on these findings , clinical testing of the BIBW2992 and rapamycin combination in non small cell lung cancer patients with Cancertumors expressing HER2 mutations is warranted .
19157502
We investigated the expression of Aurora kinases A and B by immunohistochemistry in 68 Cancerovarian carcinomas to analyze their prognostic value .
19157502
Overall , 58.8 % and 85.3 % of Cancerovarian carcinomas showed expression of Aurora A and B , respectively .
19157502
CancerTumors with Aurora A expression showed a lower rate of recurrence than those tumors without Aurora A expression ( 65 % versus 91.7 % , P = .019 ) .
19157502
Tumors with Aurora A expression showed a lower rate of recurrence than those Cancertumors without Aurora A expression ( 65 % versus 91.7 % , P = .019 ) .
19157502
In conclusion , Aurora A expression seems to have a prognostic value in Cancerovarian carcinoma .
19157633
In this study , we investigated whether single nucleotide polymorphisms ( SNPs ) in Xeroderma pigmentosum group G ( XPG ) and X-ray repair cross complementing group 1 ( XRCC1 ) were associated with the Cancertumor response in non small cell lung cancer ( NSCLC ) patients treated with platinum based chemotherapy in Chinese population .
19157633
In this study , we investigated whether single nucleotide polymorphisms ( SNPs ) in Xeroderma pigmentosum group G ( XPG ) and X-ray repair cross complementing group 1 ( XRCC1 ) were associated with the tumor response in Cancernon small cell lung cancer ( NSCLC ) patients treated with platinum based chemotherapy in Chinese population .
19221039
To evaluate the incidence and clinical impact of WT1 gene mutations in younger adult patients with cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) , sequencing of the complete coding region was performed in diagnostic samples from 617 patients who were treated on 3 German-Austrian AML Study Group protocols .
19223544
The monoclonal antibodies ( moAb ) panitumumab and cetuximab target the epidermal growth factor receptor ( EGFR ) and have proven valuable for the treatment of Cancermetastatic colorectal cancer ( mCRC ) .
19223544
When only CancerKRAS wild-type tumors were analyzed , the statistical correlation was stronger ( P = 0.016 ) .
19228619
BACKGROUND : A recent genomewide mutational analysis of Cancerglioblastomas ( World Health Organization [ WHO ] grade IV glioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of such tumors , most frequently in tumors that were known to have evolved from lower-grade gliomas ( secondary glioblastomas ) .
19228619
BACKGROUND : A recent genomewide mutational analysis of glioblastomas ( World Health Organization [ WHO ] grade IV Cancerglioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of such tumors , most frequently in tumors that were known to have evolved from lower-grade gliomas ( secondary glioblastomas ) .
19228619
BACKGROUND : A recent genomewide mutational analysis of glioblastomas ( World Health Organization [ WHO ] grade IV glioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of Cancersuch tumors , most frequently in tumors that were known to have evolved from lower-grade gliomas ( secondary glioblastomas ) .
19228619
BACKGROUND : A recent genomewide mutational analysis of glioblastomas ( World Health Organization [ WHO ] grade IV glioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of such tumors , most frequently in Cancertumors that were known to have evolved from lower-grade gliomas ( secondary glioblastomas ) .
19228619
BACKGROUND : A recent genomewide mutational analysis of glioblastomas ( World Health Organization [ WHO ] grade IV glioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of such tumors , most frequently in tumors that were known to have evolved from Cancerlower-grade gliomas ( secondary glioblastomas ) .
19228619
BACKGROUND : A recent genomewide mutational analysis of glioblastomas ( World Health Organization [ WHO ] grade IV glioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of such tumors , most frequently in tumors that were known to have evolved from lower-grade gliomas ( Cancersecondary glioblastomas ) .
19228619
METHODS : We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system ( CNS ) Cancertumors and 494 non CNS tumors .
19228619
METHODS : We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system ( CNS ) tumors and 494 Cancernon CNS tumors .
19228619
The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured Cancerglioma cells that were transfected with these genes .
19228619
RESULTS : We identified mutations that affected amino acid 132 of IDH1 in more than 70 % of WHO grade II and III Cancerastrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions .
19228619
RESULTS : We identified mutations that affected amino acid 132 of IDH1 in more than 70 % of WHO grade II and III astrocytomas and Canceroligodendrogliomas and in glioblastomas that developed from these lower-grade lesions .
19228619
RESULTS : We identified mutations that affected amino acid 132 of IDH1 in more than 70 % of WHO grade II and III astrocytomas and oligodendrogliomas and in Cancerglioblastomas that developed from these lower-grade lesions .
19228619
CancerTumors without mutations in IDH1 often had mutations affecting the analogous amino acid ( R172 ) of the IDH2 gene .
19228619
CancerTumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics , and patients with such tumors had a better outcome than those with wild-type IDH genes .
19228619
Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics , and patients with Cancersuch tumors had a better outcome than those with wild-type IDH genes .
19228619
CONCLUSIONS : Mutations of NADP ( + )-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of Cancermalignant gliomas .
19270817
von Hippel-Lindau ( VHL ) Diseasedisease is an autosomal dominant inherited tumor syndrome characterized by the development of tumors in the eye , brain , spinal cord , inner ear , adrenal gland , pancreas , kidney , and epididymis , associated with germline mutations in the VHL gene .
19270817
von Hippel-Lindau ( VHL ) disease is an autosomal dominant inherited Cancertumor syndrome characterized by the development of tumors in the eye , brain , spinal cord , inner ear , adrenal gland , pancreas , kidney , and epididymis , associated with germline mutations in the VHL gene .
19270817
von Hippel-Lindau ( VHL ) disease is an autosomal dominant inherited Diseasetumor syndrome characterized by the development of tumors in the eye , brain , spinal cord , inner ear , adrenal gland , pancreas , kidney , and epididymis , associated with germline mutations in the VHL gene .
19270817
von Hippel-Lindau ( VHL ) disease is an autosomal dominant inherited tumor syndrome characterized by the development of Cancertumors in the eye , brain , spinal cord , inner ear , adrenal gland , pancreas , kidney , and epididymis , associated with germline mutations in the VHL gene .
19273710
PURPOSE : Contrary to the extensive data accumulated regarding pancreatic carcinogenesis , the clinical and molecular features characteristic of advanced stage ( stage III and IV ) Diseasedisease are unknown .
19273710
A comprehensive study of Cancerpancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention .
19273710
A comprehensive study of pancreatic cancers from patients who have succumbed to their Diseasedisease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention .
19273710
A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this Diseasedisease and identify novel areas for intervention .
19273710
MATERIALS AND METHODS : Rapid autopsies were performed on 76 patients with documented Cancerpancreatic cancer .
19273710
The histologic features of Diseaseend stage disease were determined and correlated to the stage at initial diagnosis , patterns of failure ( locally destructive v metastatic disease ) and the status of the KRAS2 , TP53 , and DPC4 genes .
19273710
The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis , patterns of failure ( locally destructive v Diseasemetastatic disease ) and the status of the KRAS2 , TP53 , and DPC4 genes .
19273710
RESULTS : At autopsy , 30 % of patients died with locally Cancerdestructive pancreatic cancer , and 70 % died with widespread metastatic disease .
19273710
RESULTS : At autopsy , 30 % of patients died with locally destructive pancreatic cancer , and 70 % died with Diseasewidespread metastatic disease .
19273710
However , Dpc4 immunolabeling status of Cancercarcinoma tissues harvested at autopsy , a sensitive marker of DPC4 genetic status , was highly correlated with the presence of widespread metastasis but not with locally destructive tumors ( P = .007 ) .
19273710
However , Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy , a sensitive marker of DPC4 genetic status , was highly correlated with the presence of Cancerwidespread metastasis but not with locally destructive tumors ( P = .007 ) .
19273710
However , Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy , a sensitive marker of DPC4 genetic status , was highly correlated with the presence of widespread metastasis but not with locally Cancerdestructive tumors ( P = .007 ) .
19273710
CONCLUSION : CancerPancreatic cancers are represented by distinct genetic subtypes with significantly different patterns of failure .
19274060
Recent studies have shown an association between the GNAS1 T393C polymorphism and clinical outcome for Cancervarious solid tumors .
19274060
In this study , we genotyped 51 patients from an observational trial on cisplatin/5-FU-based neoadjuvant radiochemotherapy of locally Canceradvanced esophageal cancer ( cT2-4 , Nx , M0 ) and genotyping was correlated with histomorphological tumor regression .
19274060
In this study , we genotyped 51 patients from an observational trial on cisplatin/5-FU-based neoadjuvant radiochemotherapy of locally advanced esophageal cancer ( cT2-4 , Nx , M0 ) and genotyping was correlated with Cancerhistomorphological tumor regression .
19274060
The C-allele frequency in Canceresophageal cancer patients was 0.49 .
19274060
Pearson 's chi ( 2 )-test showed a significant ( P < 0.05 ) association between Cancertumor regression grades and T393C genotypes .
19274060
Overall , 63 % of the patients in the T-allele group ( TT+CT ) were minor responders with more than 10 Cancer% residual vital tumor cells in resection specimens , whereas T (-) genotypes ( CC ) showed a major histopathological response with less than 10 % residual vital tumor cells in 80 % .
19274060
Overall , 63 % of the patients in the T-allele group ( TT+CT ) were minor responders with more than 10 % residual vital tumor cells in resection specimens , whereas T (-) genotypes ( CC ) showed a major histopathological response with less than 10 Cancer% residual vital tumor cells in 80 % .
19274060
The results support the role of the T393C polymorphism as a predictive molecular marker for Cancertumor response to cisplatin/5-FU-based radiochemotherapy in esophageal cancer .
19274060
The results support the role of the T393C polymorphism as a predictive molecular marker for tumor response to cisplatin/5-FU-based radiochemotherapy in Canceresophageal cancer .
19284554
BACKGROUND : Serum levels of IGF-I in patients affected with Cancermultiple myeloma ( MM ) have been scarcely studied .
19284554
K12 ras mutation was significantly associated with Cancermalignancy , response to therapy and with significantly increased serum bFGF levels .
19287384
DiseasePolycythemia vera , essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms ( MPN ) characterized by multilineage clonal hematopoiesis .
19287384
Polycythemia vera , Diseaseessential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms ( MPN ) characterized by multilineage clonal hematopoiesis .
19287384
Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene ( JAK2 ( V617F ) ) is observed in most individuals with Diseasepolycythemia vera , essential thrombocythemia and primary myelofibrosis , there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders .
19287384
Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene ( JAK2 ( V617F ) ) is observed in most individuals with polycythemia vera , Diseaseessential thrombocythemia and primary myelofibrosis , there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders .
19287384
Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene ( JAK2 ( V617F ) ) is observed in most individuals with polycythemia vera , essential thrombocythemia and primary myelofibrosis , there likely are additional genetic events that contribute to the pathogenesis of these phenotypically Diseasedistinct disorders .
19287384
Moreover , family members of individuals with MPN are at higher AdverseOutcomerisk for the development of MPN , consistent with the existence of MPN predisposition loci .
19289619
PURPOSE : Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 ( HER-2 )-positive early and Canceradvanced breast cancer .
19289619
METHODS : Patients with CancerHER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine ( 2,500 mg/m ( 2 ) body-surface area on days 1 through 14 [ 1,250 mg/m ( 2 ) semi-daily ] ) alone or with continuation of trastuzumab ( 6 mg/kg body weight ) in 3-week cycles .
19289619
Continuation of trastuzumab beyond progression was not associated with increased Diseasetoxicity .
19289619
CONCLUSION : Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with CancerHER-2-positive breast cancer who experienced progression during trastuzumab treatment .
19304957
CEBPA mutations have been associated with improved outcome in Canceradult acute myeloid leukemia ( AML ) .
19304957
As CEBPA mutations are associated with lower relapse rate and improved survival , CEBPA mutation analysis needs to be incorporated into initial screening for AdverseOutcomerisk identification and therapy allocation at diagnosis .
19318574
FMS like tyrosine kinase 3 ( FLT3 ) inhibitors have shown activity in the treatment of Canceracute myelogenous leukemia ( AML ) .
19357394
Recently the World Health Organization ( WHO ) , in collaboration with the European Association for Haematopathology and the Society for Hematopathology , published a revised and updated edition of the WHO Classification of CancerTumors of the Hematopoietic and Lymphoid Tissues .
19357394
In this paper , the classification of myeloid neoplasms and Canceracute leukemia is highlighted with the aim of familiarizing hematologists , clinical scientists , and hematopathologists not only with the major changes in the classification but also with the rationale for those changes .
19434073
This study aims to investigate whether polymorphisms in these genes are associated with Cancertumor response and survival in cisplatin treated osteosarcoma patients .
19434073
This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin treated Cancerosteosarcoma patients .
19434073
Eight single nucleotide polymorphisms in ERCC2 , XPC , XPA , ERCC1 , ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with Cancerosteosarcoma and treated with cisplatin .
19434073
A significant association with Cancertumor response , after correction for multiple testing , was found for the Lys751Gln polymorphism in the ERCC2 gene .
19434073
This is the first pharmacogenetic study focused on Cancerosteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients .
19434073
This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in Cancerosteosarcoma patients .
19470925
METHODS We prospectively designed and conducted three phase III trials ( Four-Arm Cooperative Study , LC00-03 , and S0003 ) in advanced-stage , Cancernon-small-cell lung cancer , each with a common arm of paclitaxel plus carboplatin .
19470925
Results were assessed by Cox model for survival and by logistic regression for response and Diseasetoxicity .
19470925
Results Clinical results were similar in the two Japanese trials , and were significantly different from the US trial , for survival , Diseaseneutropenia , febrile neutropenia , and anemia .
19470925
Results Clinical results were similar in the two Japanese trials , and were significantly different from the US trial , for survival , neutropenia , Diseasefebrile neutropenia , and anemia .
19470925
Results Clinical results were similar in the two Japanese trials , and were significantly different from the US trial , for survival , neutropenia , febrile neutropenia , and Diseaseanemia .
19470925
For grade 4 Diseaseneutropenia , the HR for ABCB1 3425C -- > T was 1.84 ( 95 % CI , 0.77 to 4.48 ; P = .19 ) .
19470935
PURPOSE Mutations in the DNA damage response gene ATR ( exon 10 A10 mononucleotide repeat ) have been previously described in endometrial and Cancerother cancers with defective DNA mismatch repair .
19470935
In vitro studies showed that Cancerendometrial cancer cell lines with A10 repeat tract truncating mutations have a failure in the ATR dependent DNA damage response .
19470935
We sought to determine the frequency and clinicopathologic significance of ATR mutations in patients with Cancerendometrioid endometrial cancer .
19470935
PATIENTS AND METHODS The ATR exon 10 A10 repeat was analyzed by direct sequencing in 141 Cancertumors with microsatellite instability ( MSI positive ) and 107 microsatellite stable ( MSI negative ) tumors .
19470935
PATIENTS AND METHODS The ATR exon 10 A10 repeat was analyzed by direct sequencing in 141 tumors with microsatellite instability ( MSI positive ) and 107 microsatellite stable ( MSI negative ) Cancertumors .
19470935
Mutations occurred exclusively in CancerMSI positive tumors ( P = .02 ) , with an overall mutation rate of 8.5 % .
19470935
CONCLUSION Truncating ATR mutations in Cancerendometrial cancers are associated with biologic aggressiveness as evidenced by reduced disease-free and overall survival .
19470935
Knowledge of ATR mutation status may hold promise for individualized treatment and targeted therapies in patients with Cancerendometrial cancer .
19472011
None of these affected members had Cancerpheochromocytoma , and one had a parathyroid adenoma .
19472011
None of these affected members had pheochromocytoma , and one had a Cancerparathyroid adenoma .
19513541
PI-103 , the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin ( mTOR ) shows high antitumor activity in Cancerglioma xenografts .
19513541
In the present study , clear antitumor activity was observed with PI-103 treatment in two Cancergefitinib resistant non small cell lung cancer ( NSCLC ) cell lines , A549 and H460 , by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition .
19513541
Collectively , our results suggest that multitargeted intervention is the most Cancereffective tumor therapy , and the cooperative blockade of PI3Kalpha and mTOR with PI-103 shows promise for treating gefitinib resistant NSCLC .
19536888
BACKGROUND : CancerWilms tumor 1 ( WT1 ) is a transcription factor that is overexpressed in most acute myeloid leukemias ( AMLs ) .
19536888
BACKGROUND : Wilms tumor 1 ( WT1 ) is a transcription factor that is overexpressed in Cancermost acute myeloid leukemias ( AMLs ) .
19536888
Recently , 2 groups reported that WT1 mutations occur in approximately 10 % of normal karyotype AMLs and are an independent predictor of AdverseOutcomepoor outcome in this subgroup of patients with AML .
19536888
METHODS : The authors studied a cohort of 268 young adults ( ages 15-50 years ) with AML who were treated on the DiseaseAcute Leukemia French Association 9802 trial .
19536888
Patients who had WT1 mutations had a shorter overall survival at 4 years ( 22 % vs 56 % ; P = .01 ) and a higher AdverseOutcomerisk of recurrence at 4 years ( 82 % vs 46 % ; P = .0008 ) compared with patients who had wild-type WT1 .
19536888
Within the subgroup of patients who had normal karyotype AML ( n = 106 ) , WT1 mutation was identified as an independent adverse prognostic factor for the AdverseOutcomerisk of recurrence .
19541609
DiseasePeutz-Jeghers syndrome ( PJS ) is a familial cancer disorder due to inherited loss of function mutations in the LKB1 / STK11 serine/threonine kinase .
19541609
Peutz-Jeghers syndrome ( PJS ) is a Diseasefamilial cancer disorder due to inherited loss of function mutations in the LKB1 / STK11 serine/threonine kinase .
19541609
Peutz-Jeghers syndrome ( PJS ) is a Cancerfamilial cancer disorder due to inherited loss of function mutations in the LKB1 / STK11 serine/threonine kinase .
19541609
PJS patients develop Cancergastrointestinal hamartomas with 100 % penetrance often in the second decade of life , and demonstrate an increased predisposition toward the development of a number of additional malignancies .
19541609
PJS patients develop gastrointestinal hamartomas with 100 % penetrance often in the second decade of life , and demonstrate an increased predisposition toward the development of a number of Canceradditional malignancies .
19541609
Among mitogenic signaling pathways , the mammalian-target of rapamycin complex 1 ( mTORC1 ) pathway is hyperactivated in tissues and Cancertumors derived from LKB1 deficient mice .
19541609
Consistent with a central role for mTORC1 in these Cancertumors , rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1 +/- mice .
19541609
However , the key targets of mTORC1 in CancerLKB1 deficient tumors remain unknown .
19541609
The HIF-1alpha targets hexokinase II and Glut1 are up-regulated in these polyps , and using FDG-PET , we demonstrate that LKB1 +/- mice show increased glucose utilization in focal regions of their GI tract corresponding to these Cancergastrointestinal hamartomas .
19541609
These findings suggest a number of therapeutic modalities for the treatment and detection of Cancerhamartomas in PJS patients , and potential for the screening and treatment of the 30 % of sporadic human lung cancers bearing LKB1 mutations .
19541609
These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients , and potential for the screening and treatment of the 30 % of Cancersporadic human lung cancers bearing LKB1 mutations .
19553641
BACKGROUND : The inhibition of poly ( adenosine diphosphate [ ADP ]-ribose ) polymerase ( PARP ) is a potential synthetic lethal therapeutic strategy for the treatment of Cancercancers with specific DNA-repair defects , including those arising in carriers of a BRCA1 or BRCA2 mutation .
19553641
RESULTS : We enrolled and treated 60 patients ; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA associated Cancercancer but declined to undergo mutational testing .
19553641
Reversible dose limiting Diseasetoxicity was seen in one of eight patients receiving 400 mg twice daily ( grade 3 mood alteration and fatigue ) and two of five patients receiving 600 mg twice daily ( grade 4 thrombocytopenia and grade 3 somnolence ) .
19553641
Reversible dose limiting toxicity was seen in one of eight patients receiving 400 mg twice daily ( grade 3 mood alteration and fatigue ) and two of five patients receiving 600 mg twice daily ( grade 4 Diseasethrombocytopenia and grade 3 somnolence ) .
19553641
Pharmacokinetic data indicated rapid absorption and elimination ; pharmacodynamic studies confirmed PARP inhibition in surrogate samples ( of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles ) and Cancertumor tissue .
19553641
Objective antitumor activity was reported only in mutation carriers , all of whom had ovarian , breast , or Cancerprostate cancer and had received multiple treatment regimens .
19553641
CONCLUSIONS : Olaparib has few of the adverse effects of conventional chemotherapy , inhibits PARP , and has antitumor activity in Cancercancer associated with the BRCA1 or BRCA2 mutation .
19584151
PURPOSE : Recently , the majority of protein coding genes were sequenced in a collection of Cancerpancreatic cancers , providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas .
19584151
PURPOSE : Recently , the majority of protein coding genes were sequenced in a collection of pancreatic cancers , providing an unprecedented opportunity to identify genetic markers of prognosis for patients with Canceradenocarcinoma of the pancreas .
19584151
EXPERIMENTAL DESIGN : We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 Canceradenocarcinomas of the pancreas .
19584151
In addition , 39 genes that were mutated in more than one of these 24 Cancercancers were sequenced in a separate panel of 90 well characterized adenocarcinomas of the pancreas .
19584151
In addition , 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well characterized Canceradenocarcinomas of the pancreas .
19584151
Of these 114 patients , 89 underwent pancreaticoduodenectomy , and the somatic mutations in these Cancercancers were correlated with patient outcome .
19584151
RESULTS : When adjusted for age , lymph node status , margin status , and Cancertumor size , SMAD4 gene inactivation was significantly associated with shorter overall survival ( hazard ratio , 1.92 ; 95 % confidence interval , 1.20-3 .05 ; P = 0.006 ) .
19584151
CONCLUSIONS : SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically Cancerresected adenocarcinoma of the pancreas .
19587375
Nucleophosmin ( CancerNPM1 )-mutated acute myeloid leukemia ( AML ) , which is recognized as a provisional entity in the World Health Organization 2008 classification of myeloid neoplasms , accounts for 30 % of AML .
19587375
Paired diagnostic and relapse samples of 84 patients revealed stable NPM1 mutations in all cases , suggesting that they are pathogenetically early events and thus applicable for Diseaseminimal residual disease detection .
19636007
PURPOSE : CancerAnaplastic lymphoma kinase ( ALK ) -positive diffuse large B-cell lymphoma ( DLBCL ) is a rare variant of DLBCL that has been described only in small case reports .
19636007
PURPOSE : Anaplastic lymphoma kinase ( ALK ) Cancer-positive diffuse large B-cell lymphoma ( DLBCL ) is a rare variant of DLBCL that has been described only in small case reports .
19636007
To shed more light on the clinical and pathologic features and outcome of these Cancertumors , we reviewed data from 38 patients .
19636007
Most patients ( 60 % ) followed an aggressive clinical course with advanced stage at diagnosis , frequent marrow infiltration , and AdverseOutcomepoor outcome .
19636007
Of note , the median survival was only 12.2 months ( 95 % CI , 9.1 to 32.5 months ) in patients with Diseaseadvanced-stage disease .
19648970
We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT ( AHSCT ) for the treatment of relapsed or persistent platinum sensitive ovarian or Cancerprimary peritoneal carcinoma .
19648970
One of six patients at a topotecan dose of 4.5 mg/m ( 2 )/d and two of three patients at 6.0 mg/m ( 2 )/d had dose limiting Diseasetoxicity of grade 3 stomatitis lasting > 2 weeks .
19648970
One of six patients at a topotecan dose of 4.5 mg/m ( 2 )/d and two of three patients at 6.0 mg/m ( 2 )/d had dose limiting toxicity of grade 3 Diseasestomatitis lasting > 2 weeks .
19648970
There was no treatment related AdverseOutcomemortality .
19648970
Shorter progression-free survival was observed in Cancertumors with low topo expression ( P = 0.04 ) .
19661358
MATERIALS AND METHODS : K-ras analysis was carried out on DNA extracted from Cancerparaffin embedded tumor samples after microdissection .
19661358
RESULTS : A never reported K-ras mutation ( CAG > TAG ) determining a premature stop signal at codon 22 ( Gln22Stop ) was found in a patient with Cancermetastatic colorectal cancer .
19661358
CONCLUSION : This study is the first report of a novel K-ras truncating mutation in a patient with Cancermetastatic colorectal cancer and is also suggestive for the evaluation of alternative pathways to better identify individuals who are likely to benefit from targeted therapies .
19666869
Oncogenic pathways underlying in the development of Diseasemyelodysplastic syndromes ( MDS ) remain poorly characterized , but mutations of the ten-eleven translocation 2 ( TET2 ) gene are frequently observed .
19666869
In univariate analysis ( Cox proportional hazard model ) , the absence of TET2 mutation was associated with a 4.1-fold ( 95 % CI , 1.4-12 .0-fold ) increased AdverseOutcomerisk of death ( P = .009 ) .
19667267
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of Diseasetoxicities : thrombocytopenia , leukopenia , mucosal inflammation , hand-foot syndrome , and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
19667267
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities : Diseasethrombocytopenia , leukopenia , mucosal inflammation , hand-foot syndrome , and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
19667267
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities : thrombocytopenia , Diseaseleukopenia , mucosal inflammation , hand-foot syndrome , and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
19667267
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities : thrombocytopenia , leukopenia , Diseasemucosal inflammation , hand-foot syndrome , and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
19667267
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities : thrombocytopenia , leukopenia , mucosal inflammation , Diseasehand-foot syndrome , and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
19667267
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities : thrombocytopenia , leukopenia , mucosal inflammation , hand-foot syndrome , and any Diseasetoxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
19667267
A total of 31 single nucleotide polymorphisms in 12 candidate genes , together with several nongenetic variants , were analyzed for a possible association with Diseasetoxicity .
19667267
In addition , genetic haplotypes were developed and related to Diseasetoxicity .
19667267
RESULTS : The AdverseOutcomerisk for leukopenia was increased when the G allele in CYP1A1 2455A/G ( odds ratio [ OR ] , 6.24 ; P = .029 ) or the T allele in FLT3 738T/C ( OR , 2.8 ; P = .008 ) were present or CAG in the NR1I3 ( 5719C/T , 7738A/C , 7837T/G ) haplotype ( OR , 1.74 ; P = .041 ) was absent .
19667267
RESULTS : The risk for Diseaseleukopenia was increased when the G allele in CYP1A1 2455A/G ( odds ratio [ OR ] , 6.24 ; P = .029 ) or the T allele in FLT3 738T/C ( OR , 2.8 ; P = .008 ) were present or CAG in the NR1I3 ( 5719C/T , 7738A/C , 7837T/G ) haplotype ( OR , 1.74 ; P = .041 ) was absent .
19667267
Any Diseasetoxicity higher than grade 2 prevalence was increased when the T allele of vascular endothelial growth factor receptor 2 1191C/T ( OR , 2.39 ; P = .046 ) or a copy of TT in the ABCG2 (-15622C/T , 1143C/T ) haplotype ( OR , 2.63 ; P = .016 ) were present .
19667267
The AdverseOutcomerisk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G ( OR , 4.03 ; P = .021 ) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 ( 3435C/T , 1236C/T , 2677G/T ) haplotype ( OR , 2.56 ; P = .035 ) was present .
19667267
The risk for Diseasemucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G ( OR , 4.03 ; P = .021 ) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 ( 3435C/T , 1236C/T , 2677G/T ) haplotype ( OR , 2.56 ; P = .035 ) was present .
19667267
The risk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G ( OR , 4.03 ; P = .021 ) and the prevalence of Diseasehand-foot syndrome was increased when a copy of TTT in the ABCB1 ( 3435C/T , 1236C/T , 2677G/T ) haplotype ( OR , 2.56 ; P = .035 ) was present .
19667267
CONCLUSION : This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes , efflux transporters , and drug targets are associated with Diseasesunitinib related toxicities .
19667267
A better understanding of genetic and nongenetic determinants of Diseasesunitinib toxicity should help to optimize drug treatment in individual patients .
19671763
Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal , acral lentiginous , and chronically sun damaged Cancermelanomas .
19671763
We have identified the Cancerfirst human melanoma cell line with an endogenous L576P mutation , the most common KIT mutation in melanoma ( approximately 30-40 % ) .
19671763
We have identified the first human melanoma cell line with an endogenous L576P mutation , the most common KIT mutation in Cancermelanoma ( approximately 30-40 % ) .
19671763
Two Cancermetastatic melanoma patients with the L576P KIT mutation were treated with dasatinib , including one patient previously treated with imatinib .
19671763
Both patients had marked reduction ( > 50 % ) and elimination of Cancertumor F18-fluorodeoxyglucose ( FDG )-avidity by positron emission tomography ( PET ) imaging after dasatinib treatment .
19671763
These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in Cancermelanoma , and thus has therapeutic implications for acrallentiginous , chronic sun damaged , and mucosal melanomas .
19671763
These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma , and thus has therapeutic implications for acrallentiginous , chronic sun damaged , and Cancermucosal melanomas .
19706758
We investigated the genotype dependent therapeutic potential of targeting the phosphoinositide 3-kinase ( PI3K )/Akt pathway for Cancerthyroid cancer .
19706758
Growth of Cancerxenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine .
19706758
Thus , this work for the first time shows that genetic alterations in the PI3K and Akt pathway confer Cancerthyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR .
19706758
This genotype based targeting of the PI3K and Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for Cancerthyroid cancer and warrants further studies .
19718025
We performed a mutational analysis of the protein tyrosine kinase ( PTK ) gene family in Cancercutaneous metastatic melanoma .
19718025
We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 Cancermelanoma samples .
19718025
We found ERBB4 mutations in 19 % of individuals with Cancermelanoma and found mutations in two other kinases ( FLT1 and PTK2B ) in 10 % of individuals with melanomas .
19718025
We found ERBB4 mutations in 19 % of individuals with melanoma and found mutations in two other kinases ( FLT1 and PTK2B ) in 10 % of individuals with Cancermelanomas .
19718025
CancerMelanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib .
19718025
These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in Cancerindividual melanomas .
19723655
Angiosarcomas ( AS ) represent a heterogeneous group of Cancermalignant vascular tumors occurring not only in different anatomic locations but also in distinct clinical settings , such as radiation or associated chronic lymphedema .
19723655
Although representing only 1 % to 2 % of Cancersoft tissue sarcomas , vascular sarcomas provide unique insight into the general process of tumor angiogenesis .
19723655
Although representing only 1 % to 2 % of soft tissue sarcomas , Cancervascular sarcomas provide unique insight into the general process of tumor angiogenesis .
19723655
Although representing only 1 % to 2 % of soft tissue sarcomas , vascular sarcomas provide unique insight into the general process of Cancertumor angiogenesis .
19726788
The Hedgehog ( Hh ) signaling pathway is inappropriately activated in Cancercertain human cancers , including medulloblastoma , an aggressive brain tumor .
19726788
The Hedgehog ( Hh ) signaling pathway is inappropriately activated in certain human cancers , including Cancermedulloblastoma , an aggressive brain tumor .
19726788
The Hedgehog ( Hh ) signaling pathway is inappropriately activated in certain human cancers , including medulloblastoma , an Canceraggressive brain tumor .
19726788
GDC-0449 , a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened ( SMO ) , has produced promising anti-tumor responses in early clinical studies of Cancercancers driven by mutations in this pathway .
19726788
To evaluate the mechanism of resistance in a Cancermedulloblastoma patient who had relapsed after an initial response to GDC-0449 , we determined the mutational status of Hh signaling genes in the tumor after disease progression .
19726788
To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449 , we determined the mutational status of Hh signaling genes in the Cancertumor after disease progression .
19726788
To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449 , we determined the mutational status of Hh signaling genes in the tumor after Diseasedisease progression .
19726788
A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of Cancermedulloblastoma .
19726788
These findings show that acquired mutations in a serpentine receptor with features of a G protein coupled receptor can serve as a mechanism of drug resistance in Cancerhuman cancer .
19737969
The echinoderm microtubule associated protein like Cancer4-anaplastic lymphoma kinase ( EML4-ALK ) fusion gene has been identified as an oncogene in a subset of non small cell lung cancers ( NSCLC ) .
19737969
The echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase ( EML4-ALK ) fusion gene has been identified as an oncogene in a subset of Cancernon small cell lung cancers ( NSCLC ) .
19737969
We used profiling of Cancercancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements .
19737969
This approach led to the detection of EML4-ALK fusion in breast and Cancercolorectal carcinomas in addition to NSCLC .
19737969
Screening of a large collection of Cancerpatient tumor samples showed the presence of EML4-ALK fusion in 2.4 % of breast ( 5 of 209 ) , 2.4 % of colorectal ( 2 of 83 ) , and in 11.3 % of NSCLC ( 12 of 106 ) .
19737969
Besides previously known EML4-ALK variants 1 ( E13 ; A20 ) and 2 ( E20 ; A20 ) , a novel variant E21 ; A20 was found in Cancercolorectal carcinoma .
19737969
The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in Cancertumor samples representative of breast , colon , and NSCLC .
19737969
EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay , which revealed its substantial heterogeneity in both Cancerprimary tumors and tumor derived cell lines .
19737969
EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay , which revealed its substantial heterogeneity in both primary tumors and Cancertumor derived cell lines .
19737969
Collectively , these findings show the recurrence of EML4-ALK fusion in Cancermultiple solid tumors and further substantiate its role in tumorigenesis .
19770381
PURPOSE : The causes of the aggressive nature of CancerBCR-ABL1-positive adult acute lymphoblastic leukemia ( ALL ) are unknown .
19770381
PATIENTS AND METHODS : Eighty-three patients with de novo adult Philadelphia chromosome ( Ph ) -positive ALL were enrolled onto institutional ( n = 17 ) or Gruppo Italiano Malattie Ematologiche Maligne dell ' Adulto Working Party delle DiseaseLeucemia Acute ( n = 66 ) clinical trials .
19775480
BACKGROUND : Thymidylate synthase ( TS ) and Topoisomerase I ( Topo I ) are significant biomarkers in Cancercolorectal cancer ( CRC ) .
19775480
CancerArchival paraffin embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I .
19775480
The results were correlated with survival ( OS ) and Diseasedisease free survival ( DFS ) .
19775480
In multivariate analysis however , Topo I expression was associated with a AdverseOutcomereduced risk of death ( HR = 0.61 , 95 % CI 0.42-0 .88 , p = 0.009 ) .
19794967
We tested this hypothesis in Cancerlung cancer patients treated with tyrosine kinase inhibitors ( TKIs ) .
19794967
Eighty-three patients with Cancerlung adenocarcinoma treated with erlotinib or gefitinib were included in this study .
19794967
DS detected KRAS mutations in 16 ( 19 % ) of 83 Cancertumors ; ME sequencing identified all the mutations detected by DS but also mutations in minor clones of 14 additional tumors , for a total of 30 ( 36 % ) of 83 .
19794967
DS detected KRAS mutations in 16 ( 19 % ) of 83 tumors ; ME sequencing identified all the mutations detected by DS but also mutations in minor clones of 14 Canceradditional tumors , for a total of 30 ( 36 % ) of 83 .
19794967
KRAS mutations in minor clones have an important impact on response and survival of patients with Cancerlung adenocarcinoma treated with EGFR-TKI .
19840887
PURPOSE : This study evaluated efficacy of single-agent trastuzumab against advanced or Cancerrecurrent HER2 positive endometrial carcinoma ( EC ) , and explored predictors for HER2 amplification .
19840887
CancerTumors were required to have HER2 overexpression ( 2+ or 3+ immunohistochemical staining ) or HER2 amplification ( FISH HER2 and CEP 17 ratio > 2.0 ) .
19840887
Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1 , then 2 mg/kg weekly until Diseasedisease progression .
19840887
The primary endpoint was Cancertumor response .
19840887
RESULTS : Of the 286 Cancertumors centrally screened by LabCorp , 33 ( 11.5 % ) were HER2 amplified .
19840887
Three of 8 clear ( 38 % ) Cancercell carcinomas and 7 of 25 serous carcinomas ( 28 % ) screened exhibited HER2 amplification compared with 7 % ( 2/29 ) of endometrioid adenocarcinomas .
19840887
Three of 8 clear ( 38 % ) cell carcinomas and 7 of 25 Cancerserous carcinomas ( 28 % ) screened exhibited HER2 amplification compared with 7 % ( 2/29 ) of endometrioid adenocarcinomas .
19840887
Three of 8 clear ( 38 % ) cell carcinomas and 7 of 25 serous carcinomas ( 28 % ) screened exhibited HER2 amplification compared with 7 % ( 2/29 ) of Cancerendometrioid adenocarcinomas .
19840887
Thirty-four women were enrolled ; 1 was excluded ( refused treatment ) ; and 18 had Cancertumors with known HER2 amplification .
19840887
No Cancermajor tumor responses were observed .
19840887
Twelve women experienced Diseasestable disease , 18 had increasing disease , and 3 were indeterminate for tumor response .
19840887
Twelve women experienced stable disease , 18 had increasing Diseasedisease , and 3 were indeterminate for tumor response .
19840887
Twelve women experienced stable disease , 18 had increasing disease , and 3 were indeterminate for Cancertumor response .
19840887
CONCLUSION : Trastuzumab as a single agent did not demonstrate activity against Cancerendometrial carcinomas with HER2 overexpression or HER2 amplification , although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment .
19840887
CONCLUSION : Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification , although full planned accrual of women with HER2 amplified Cancertumors was not achieved due to slow recruitment .
19840887
Serous and Cancerclear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification .
19874578
INTRODUCTION : Alterations in cell cycle regulators have been implicated in Cancerhuman malignancies including breast cancer .
19874578
INTRODUCTION : Alterations in cell cycle regulators have been implicated in human malignancies including Cancerbreast cancer .
19874578
PD 0332991 is an orally active , highly selective inhibitor of the cyclin D kinases ( CDK ) 4 and CDK6 with ability to block Cancerretinoblastoma ( Rb ) phosphorylation in the low nanomolar range .
19874578
To identify predictors of response , we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized Cancerhuman breast cancer cell lines .
19874578
METHODS : Forty-seven Cancerhuman breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values .
19874578
METHODS : Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of Cancerbreast cancer were treated with PD 0332991 to determine IC50 values .
19874578
CONCLUSIONS : These studies suggest a role for CDK4/6 inhibition in some Cancerbreast cancers and identify criteria for patient selection in clinical studies of PD 0332991
19901104
PURPOSE : O6-methylguanine-methyltransferase ( MGMT ) promoter methylation has been shown to predict survival of patients with Cancerglioblastomas if temozolomide is added to radiotherapy ( RT ) .
19901104
It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine , lomustine , and vincristine ( PCV ) chemotherapy in patients with Canceranaplastic oligodendroglial tumors ( AOT ) .
19901104
PATIENTS AND METHODS : In the European Organisation for the Research and Treatment of CancerCancer study 26951 , 368 patients with AOT were randomly assigned to either RT alone or to RT followed by adjuvant PCV .
19901104
From 165 patients of this study , formalin fixed , Cancerparaffin embedded tumor tissue was available for MGMT promoter methylation analysis .
19901104
In multivariate analysis , MGMT promoter methylation , 1p/19q codeletion , Cancertumor necrosis , and extent of resection were independent prognostic factors .
19901104
In Cancertumors diagnosed at central pathology review as glioblastoma , no prognostic effect of MGMT promoter methylation was observed .
19901104
In tumors diagnosed at central pathology review as Cancerglioblastoma , no prognostic effect of MGMT promoter methylation was observed .
19901104
The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with Cancerglioblastoma .
19903786
PURPOSE : Identifying Cancerrectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy .
19903786
PURPOSE : Identifying rectal cancer patients at AdverseOutcomerisk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy .
19903786
PIK3CA , KRAS , and BRAF mutations are commonly found in Cancercolon cancers , but their prevalence has not been clearly assessed in rectal cancer .
19903786
PIK3CA , KRAS , and BRAF mutations are commonly found in colon cancers , but their prevalence has not been clearly assessed in Cancerrectal cancer .
19903786
In this study , we aim to determine the mutation frequencies of PIK3CA , KRAS , and BRAF and to investigate whether a mutation may be used as a prognostic parameter in Cancerrectal cancer patients .
19903786
EXPERIMENTAL DESIGN : We evaluated DNA mutations in PIK3CA , KRAS , and BRAF in 240 stage I to III Cancerrectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial .
19903786
RESULTS : PIK3CA , KRAS , and BRAF mutations were identified in 19 ( 7.9 % ) , 81 ( 33.9 % ) , and 5 ( 2.1 % ) Cancerrectal cancers .
19903786
Patients with PIK3CA mutations developed more local recurrences ( AdverseOutcome5-year risks , 27.8 % versus 9.4 % ; P = 0.006 ) and tended to develop these recurrences more rapidly after surgery ( median local recurrence-free interval since surgery : 7.9 versus 19.6 months ; P = 0.07 ) than patients without PIK3CA mutations .
19903786
CONCLUSION : PIK3CA mutations can be used as a biomarker in identifying Cancerrectal cancer patients with an increased risk for local recurrences .
19903786
CONCLUSION : PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an AdverseOutcomeincreased risk for local recurrences .
19915144
Genetic alterations that activate the mitogen activated protein kinase ( MAP kinase ) pathway occur commonly in Cancercancer .
19915144
For example , the majority of Cancermelanomas harbor mutations in the BRAF oncogene , which are predicted to confer enhanced sensitivity to pharmacologic MAP kinase inhibition ( e.g. , RAF or MEK inhibitors ) .
19915144
We investigated the clinical relevance of MEK dependency in Cancermelanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro , as well as tumors obtained from relapsed patients following treatment with AZD6244 , an allosteric MEK inhibitor .
19915144
We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro , as well as Cancertumors obtained from relapsed patients following treatment with AZD6244 , an allosteric MEK inhibitor .
19915144
Other mutations affected MEK1 codons located within or abutting the N-terminal negative regulatory helix ( helix A ) , which also undergo gain-of-function germline mutations in cardio-facio-cutaneous ( CFC ) Diseasesyndrome .
19915144
One such mutation , MEK1 ( P124L ) , was identified in a resistant metastatic focus that emerged in a Cancermelanoma patient treated with AZD6244 .
19915144
However , exposing CancerBRAF-mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones .
19915144
These results affirm the importance of MEK dependency in CancerBRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications .
19922504
Glutathione S-transferase P1 ( GSTP1 ) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and Diseasetoxicity of platinum based chemotherapy .
19922504
We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with Cancermetastatic colorectal carcinoma who had been treated with first-line FOLFOX-4 .
19922504
In combined analysis , patients without any AdverseOutcomerisk genotype , including GSTP1-105 Ile and Ile , ERCC1-118 C/T or T/T , and XPD-751 Lys and Gln , had significantly longer progression-free and overall survivals ( P < 0.01 ) .
19933982
BACKGROUND : Mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) have been implicated in tumorigenesis of Cancergliomas .
19933982
Patients with Cancerhigh-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival , but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment .
19933982
Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival , but it is unknown if this improved survival also holds for Cancerlow-grade astrocytoma and whether these mutations predict outcome to specific treatment .
19933982
METHODS : We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with Cancerdedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy .
19933982
RESULTS : IDH1 mutations were present in 86 % of the 49 Cancerprogressive astrocytomas .
19933982
CONCLUSION : These results indicate that IDH1 mutations identify a subgroup of Cancergliomas with an improved survival , but are unrelated to the temozolomide response .
19934290
KRAS mutation in Cancermetastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor ( EGFR )-targeted therapy ( cetuximab or panitumumab ) .
19934290
It remains uncertain , however , whether KRAS mutation predicts prognosis or clinical outcome of Cancercolon cancer patients independent of anti-EGFR therapy .
19934290
METHODS : We conducted a study of 508 cases identified among 1,264 patients with stage III Cancercolon cancer who enrolled in a randomized adjuvant chemotherapy trial ( 5-fluorouracil , leucovorin with or without irinotecan ) in 1999-2001 ( CALGB 89803 ) .
19934290
KRAS mutations were detected in 178 Cancertumors ( 35 % ) by pyrosequencing .
19934290
Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age , sex , Cancertumor location , tumor and node stage , performance status , adjuvant chemotherapy arm , and microsatellite instability status .
19934290
Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age , sex , tumor location , Cancertumor and node stage , performance status , adjuvant chemotherapy arm , and microsatellite instability status .
19934290
RESULTS : Compared with patients with CancerKRAS-wild-type tumors , patients with KRAS mutated tumors did not experience any difference in disease-free , recurrence-free , or overall survival .
19934290
RESULTS : Compared with patients with KRAS-wild-type tumors , patients with KRAS mutated Cancertumors did not experience any difference in disease-free , recurrence-free , or overall survival .
19934290
CONCLUSIONS : In this large trial of chemotherapy in stage III Cancercolon cancer patients , KRAS mutational status was not associated with any significant influence on disease-free or overall survival .
19941080
BACKGROUND : Response to chemotherapy and anatomical spread are significant prognostic factors in patients with Canceresophageal squamous cell carcinoma ( ESCC ) treated by chemotherapy then surgery .
19941080
Predicting the response to chemotherapy would allow significant optimization of Cancercancer treatment .
19941080
RESULTS : The retrospective study showed mutant p53 genotype and positive p53 IHC staining in 46.8 and 55.8 % of patients , respectively , which was not associated with patient 's clinicopathological findings including Cancerinitial tumor stage .
19965647
We investigated the benefit of adding all-trans retinoic acid ( ATRA ) to chemotherapy for younger patients with Cancernonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome , and considered interactions between treatment and molecular markers .
19965647
We investigated the benefit of adding all-trans retinoic acid ( ATRA ) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and Diseasehigh-risk myelodysplastic syndrome , and considered interactions between treatment and molecular markers .
19966866
Germline TSC1 or TSC2 mutations cause tuberous sclerosis complex ( TSC ) , a Cancerhamartoma syndrome with lung involvement .
19966866
Germline TSC1 or TSC2 mutations cause tuberous sclerosis complex ( TSC ) , a Diseasehamartoma syndrome with lung involvement .
19966866
To explore the potential interaction between TSC1 and KRAS activation in Cancerlung cancer , mice in which Tsc1 loss and Kras ( G12D ) expression occur in a small fraction of lung epithelial cells were generated .
19966866
Mice with a combined Tsc1-Kras ( G12D ) mutation had dramatically reduced Cancertumor latency ( median survival : 11.6-15 .6 weeks ) in comparison with Kras ( G12D ) alone mutant mice ( median survival : 27.5 weeks ) .
19966866
Tsc1-Kras ( G12D ) Cancertumors showed consistent activation of mTOR ( mammalian target of rapamycin ) C1 and responded to treatment with rapamycin , leading to significantly improved survival , whereas rapamycin had minor effects on cancers in Kras ( G12D ) alone mice .
19966866
Tsc1-Kras ( G12D ) tumors showed consistent activation of mTOR ( mammalian target of rapamycin ) C1 and responded to treatment with rapamycin , leading to significantly improved survival , whereas rapamycin had minor effects on Cancercancers in Kras ( G12D ) alone mice .
19966866
Loss of heterozygosity for TSC1 or TSC2 was found in 22 % of 86 Cancerhuman lung cancer specimens .
19966866
However , none of the 80 Cancerlung cancer lines studied showed evidence of the lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss .
19966866
These data indicate that Tsc1 loss synergizes with the Kras mutation to enhance lung tumorigenesis in the mouse , but that this is a rare event in Cancerhuman lung cancer .
19966866
Rapamycin may have unique benefit for patients with Cancerlung cancer , for whom the TSC1 and TSC2 function is limited .
20007775
Both Numb and Notch have been implicated in Cancerhuman tumors .
20007775
Here , we show that Notch signaling is altered in approximately one third of Cancernon-small-cell lung carcinomas ( NSCLCs ) , which are the leading cause of cancer related deaths : in approximately 30 % of NSCLCs , loss of Numb expression leads to increased Notch activity , while in a smaller fraction of cases ( around 10 % ) , gain-of-function mutations of the NOTCH-1 gene are present .
20007775
Here , we show that Notch signaling is altered in approximately one third of non-small-cell lung carcinomas ( NSCLCs ) , which are the leading cause of Cancercancer related deaths : in approximately 30 % of NSCLCs , loss of Numb expression leads to increased Notch activity , while in a smaller fraction of cases ( around 10 % ) , gain-of-function mutations of the NOTCH-1 gene are present .
20007775
Finally , primary epithelial cell cultures , derived from NSCLC harboring constitutive activation of the Notch pathway , are selectively killed by inhibitors of Notch ( gamma-secretase inhibitors ) , showing that the proliferative advantage of these Cancertumors is dependent upon Notch signaling .
20007775
Our results show that the deregulation of the Notch pathway is a relatively frequent event in NSCLCs and suggest that it might represent a possible target for molecular therapies in these Cancertumors .
20026798
PURPOSE : To analyze the prognostic significance of NPM1 mutations , and the associated gene- and microRNA expression signatures in older patients with de novo , cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) treated with intensive chemotherapy .
20026798
PATIENTS AND METHODS : One hundred forty-eight adults age > or = 60 years with de novo CN-AML , enrolled onto CancerCancer and Leukemia Group B protocols 9720 and 10201 , were studied at diagnosis for NPM1 , FLT3 , CEBPA , and WT1 mutations , and gene- and microRNA expression profiles .
20026798
PATIENTS AND METHODS : One hundred forty-eight adults age > or = 60 years with de novo CN-AML , enrolled onto Cancer and DiseaseLeukemia Group B protocols 9720 and 10201 , were studied at diagnosis for NPM1 , FLT3 , CEBPA , and WT1 mutations , and gene- and microRNA expression profiles .
20038723
PURPOSE In the phase III INTEREST trial , 1,466 pretreated patients with Canceradvanced non small cell lung cancer ( NSCLC ) were randomly assigned to receive gefitinib or docetaxel .
20038723
As a preplanned analysis , we prospectively analyzed Canceravailable tumor biopsies to investigate the relationship between biomarkers and clinical outcomes .
20081860
CancerFollicular lymphoma ( FL ) and the GCB subtype of diffuse large B-cell lymphoma ( DLBCL ) derive from germinal center B cells .
20081860
Follicular lymphoma ( FL ) and the GCB subtype of Cancerdiffuse large B-cell lymphoma ( DLBCL ) derive from germinal center B cells .
20081860
After the recent discovery of mutations in KDM6A ( UTX ) , which encodes the histone H3K27me3 demethylase UTX , in Cancerseveral cancer types , EZH2 is the second histone methyltransferase gene found to be mutated in cancer .
20081860
After the recent discovery of mutations in KDM6A ( UTX ) , which encodes the histone H3K27me3 demethylase UTX , in several cancer types , EZH2 is the second histone methyltransferase gene found to be mutated in Cancercancer .
20085938
The phosphatidylinositol 3-kinase ( PI3K ) signaling axis impacts on Cancercancer cell growth , survival , motility , and metabolism .
20085938
This pathway is activated by several different mechanisms in Cancercancers , including somatic mutation and amplification of genes encoding key components .
20085938
In addition , PI3K signaling may serve integral functions for noncancerous cells in the Cancertumor microenvironment .
20085938
In this review , we will discuss how PI3K signaling affects the growth and survival of Cancertumor cells .
20085938
From this vantage , we will consider how inhibitors of the PI3K signaling cascade , either alone or in combination with other therapeutics , can most effectively be used for the treatment of Cancercancer .
20088962
The aim of this study was to establish Cancernew biliary tract carcinoma ( BTC ) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy .
20088962
Based on their gemcitabine sensitivity , 10 BTC cell lines ( including six new and four publicly available ones ) were clearly categorized into two groups , and MAGEH1 mRNA expression in the Cancertumor cells showed a significant negative correlation with their sensitivity to gemcitabine .
20124187
EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2 positive , Cancertrastuzumab-refractory metastatic breast cancer ( MBC ) .
20124187
Secondary efficacy end points included overall response rate ( ORR ) , clinical benefit rate ( CBR ; complete response , partial response , and Diseasestable disease for >/= 24 weeks ) , and overall survival ( OS ) .
20124187
CONCLUSION : Despite Diseasedisease progression on prior trastuzumab based therapy , lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone , thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2 positive MBC .
20127344
Somatic mutations in the isocitrate dehydrogenase 1 gene ( IDH1 ) occur at high frequency in Cancergliomas and seem to be a prognostic factor for survival in glioblastoma patients .
20127344
Somatic mutations in the isocitrate dehydrogenase 1 gene ( IDH1 ) occur at high frequency in gliomas and seem to be a prognostic factor for survival in Cancerglioblastoma patients .
20127344
In our set of 98 Cancerglioblastoma patients , IDH1 ( R132 ) mutations were associated with improved survival of 1 year on average , after correcting for age and other variables with Cox proportional hazards models .
20127344
Mutated IDH1 has a gain of function to produce 2-hydroxyglutarate by NADPH dependent reduction of alpha-ketoglutarate , but it is unknown whether NADPH production in Cancergliomas is affected by IDH1 mutations .
20127344
We assessed the effect of IDH1 ( R132 ) mutations on IDH mediated NADPH production in Cancerglioblastomas in situ .
20127344
Metabolic mapping and image analysis was applied to 51 Cancerglioblastoma samples of which 16 carried an IDH1 ( R132 ) mutation .
20127344
twofold diminished NADP +-dependent IDH activity , whereas activity of NAD +-dependent IDH and the other NADP +-dependent dehydrogenases was not affected in situ in Cancerglioblastoma .
20127344
The total NADPH production capacity in Cancerglioblastoma was provided for 65 % by IDH activity and the occurrence of IDH1 ( R132 ) mutation reduced this capacity by 38 % .
20127344
It is concluded that NADPH production is hampered in Cancerglioblastoma with IDH1 ( R132 ) mutation .
20127344
The low NADPH levels may sensitize Cancerglioblastoma to irradiation and chemotherapy , thus explaining the prolonged survival of patients with mutated glioblastoma .
20127344
The low NADPH levels may sensitize glioblastoma to irradiation and chemotherapy , thus explaining the prolonged survival of patients with mutated Cancerglioblastoma .
20141835
Kinase-dead BRAF mimics the effects of the BRAF selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce Cancermelanoma in mice .
20141835
Our data reveal another paradigm of BRAF mediated signaling that promotes Cancertumor progression .
20141835
They highlight the importance of understanding pathway signaling in clinical practice and of genotyping Cancertumors prior to administering BRAF selective drugs , to identify patients who are likely to respond and also to identify patients who may experience adverse effects .
20142587
CONCLUSION : Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naive patients who had advanced , CancerErbB2 positive breast cancer .
20151405
Mutations in the von Hippel-Lindau ( VHL ) gene are responsible for DiseaseVHL disease , congenital polycythemia , and are found in many sporadic tumor types as well .
20151405
Mutations in the von Hippel-Lindau ( VHL ) gene are responsible for VHL disease , Diseasecongenital polycythemia , and are found in many sporadic tumor types as well .
20151405
Mutations in the von Hippel-Lindau ( VHL ) gene are responsible for VHL disease , congenital polycythemia , and are found in Cancermany sporadic tumor types as well .
20151405
We also review DiseaseVHL disease , known and theorized pathogenesis of common VHL manifestations , and genotype-phenotype correlations .
20151405
Analysis of all VHL families , excluding germline mutations resulting in Diseasecongenital polycythemias , describes the spectrum of mutation types : 52 % missense , 13 % frameshift , 11 % nonsense , 6 % in-frame deletions and insertions , 11 % large and complete deletions , and 7 % splice mutations .
20165957
Tuberous sclerosis complex ( TSC ) is an Diseaseautosomal dominant neurocutaneous syndrome caused by mutations in TSC1 and TSC2 .
20179196
Amplification of fibroblast growth factor receptor 1 ( FGFR1 ) occurs in approximately 10 % of Cancerbreast cancers and is associated with poor prognosis .
20179196
Amplification of fibroblast growth factor receptor 1 ( FGFR1 ) occurs in approximately 10 % of breast cancers and is associated with AdverseOutcomepoor prognosis .
20179196
However , it is uncertain whether overexpression of FGFR1 is causally linked to the AdverseOutcomepoor prognosis of amplified cancers .
20179196
However , it is uncertain whether overexpression of FGFR1 is causally linked to the poor prognosis of amplified Cancercancers .
20179196
Here , we show that FGFR1 overexpression is robustly associated with FGFR1 amplification in two independent series of Cancerbreast cancers .
20179196
CancerBreast cancer cell lines with FGFR1 overexpression and amplification show enhanced ligand dependent signaling , with increased activation of the mitogen activated protein kinase and phosphoinositide 3-kinase-AKT signaling pathways in response to FGF2 , but also show basal ligand independent signaling , and are dependent on FGFR signaling for anchorage independent growth .
20179196
FGFR1 signaling suppresses progesterone receptor ( PR ) expression in vitro , and likewise , amplified Cancercancers are frequently PR negative , identifying a potential biomarker for FGFR1 activity .
20179196
Furthermore , we show that amplified Cancercancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16 % to 27 % of luminal B-type breast cancers .
20179196
Furthermore , we show that amplified cancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16 % to 27 % of Cancerluminal B-type breast cancers .
20179196
Our data suggest that amplification and overexpression of FGFR1 may be a major contributor to AdverseOutcomepoor prognosis in luminal-type breast cancers , driving anchorage independent proliferation and endocrine therapy resistance .
20179196
Our data suggest that amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in Cancerluminal-type breast cancers , driving anchorage independent proliferation and endocrine therapy resistance .
20227043
CancerOvarian cancer is a leading cause of death from gynecologic malignancies .
20227043
Ovarian cancer is a leading cause of death from Cancergynecologic malignancies .
20227043
Treatment for Diseaseadvanced-stage disease remains limited and , to date , targeted therapies have been incompletely explored .
20227043
By systematically suppressing each human tyrosine kinase in Cancerovarian cancer cell lines by RNAi , we found that an autocrine signal transducing loop involving NRG1 and activated ErbB3 operates in a subset of primary ovarian cancers and ovarian cancer cell lines .
20227043
By systematically suppressing each human tyrosine kinase in ovarian cancer cell lines by RNAi , we found that an autocrine signal transducing loop involving NRG1 and activated ErbB3 operates in a subset of Cancerprimary ovarian cancers and ovarian cancer cell lines .
20227043
By systematically suppressing each human tyrosine kinase in ovarian cancer cell lines by RNAi , we found that an autocrine signal transducing loop involving NRG1 and activated ErbB3 operates in a subset of primary ovarian cancers and Cancerovarian cancer cell lines .
20227043
Perturbation of this circuit with ErbB3 directed RNAi decreased cell growth in three-dimensional culture and resulted in decreased Diseasedisease progression and prolonged survival in a xenograft mouse model of ovarian cancer .
20227043
Perturbation of this circuit with ErbB3 directed RNAi decreased cell growth in three-dimensional culture and resulted in decreased disease progression and prolonged survival in a xenograft mouse model of Cancerovarian cancer .
20227043
Furthermore , a monoclonal ErbB3 directed antibody ( MM-121 ) also significantly inhibited Cancertumor growth in vivo .
20227043
These findings identify ErbB3 as a potential therapeutic target in Cancerovarian cancer .
20336784
BACKGROUND : This study examined the clinical significance of CCNE1 ( Cyclin E1 ) amplification and assessed whether CCNE1 is a potential therapeutic target in Cancerovarian cancer .
20336784
METHODS : CCNE1 expression and amplification in Cancerovarian cancer was assessed by immunohistochemistry , fluorescence in situ hybridization and clinical data collected by retrospective chart review .
20336784
CCNE1 gene knockdown using silencing RNA and a CCNE1 gene transfection system were used to asses CCNE1 function in tissue samples of Cancerovarian cancer .
20336784
RESULTS : Gene amplification was identified in 18 ( 20.4 % ) of 88 Cancerovarian carcinomas .
20336784
Profound growth inhibition and apoptosis were observed in silencing RNA treated Cancercancer cells with gene amplification compared with results in cancer cells with CCNE1 moderate expression without gene amplification or with low CCNE1 expression .
20336784
Profound growth inhibition and apoptosis were observed in silencing RNA treated cancer cells with gene amplification compared with results in Cancercancer cells with CCNE1 moderate expression without gene amplification or with low CCNE1 expression .
20336784
CCNE1 overexpression stimulated proliferation in Cancerovarian cancer cell lines ES2 and TOV-21G , which have lower endogenous CCNE1 expression .
20336784
CONCLUSIONS : These findings indicate that CCNE1 overexpression is critical to growth and survival of Cancerovarian cancer tumors with CCNE1 gene amplification .
20336784
Furthermore , they suggest that CCNE1 silencing RNA induced phenotypes depend on amplification status of Cancerovarian cancers .
20336784
Therefore , CCNE1 targeted therapy may benefit Cancerovarian cancer patients with CCNE1 amplification .
20354191
Activation of cyclin dependent kinases 4 and 6 ( cdk4/6 ) occurs in the majority of Cancerglioblastoma multiforme ( GBM ) tumors , and represents a promising molecular target for the development of small molecule inhibitors .
20354191
Activation of cyclin dependent kinases 4 and 6 ( cdk4/6 ) occurs in the majority of glioblastoma multiforme ( GBM ) Cancertumors , and represents a promising molecular target for the development of small molecule inhibitors .
20354191
In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G ( 1 ) cell cycle arrest and induction of senescence in each of 16 Cancerretinoblastoma protein ( Rb )-proficient cell lines regardless of other genetic lesions , whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment .
20354191
PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of Cancerintracranial GBM xenograft tumors , including those that had recurred after initial therapy with temozolomide .
20354191
Remarkably , no mice receiving PD-0332991 died as a result of Diseasedisease progression while on therapy .
20363910
Tissue hypoxia commonly occurs in Cancertumors .
20363910
Hypoxia- inducible factor ( HIF ) -1 and HIF-2 , which are essential mediators of cellular response to hypoxia , regulate gene expression for Cancertumor angiogenesis , glucose metabolism , and resistance to oxidative stress .
20363910
Their key regulatory subunits , HIF1A ( HIF-1alpha ) and endothelial PAS domain protein 1 ( EPAS1 ; HIF-2alpha ) , are overexpressed and associated with patient prognosis in a variety of Cancercancers .
20363910
However , prognostic or molecular features of Cancercolon cancer with HIF expression remain uncertain .
20363910
Among 731 Cancercolorectal cancers in two prospective cohort studies , 142 ( 19 % ) tumors showed HIF1A overexpression , and 322 ( 46 % ) showed EPAS1 overexpression by immunohistochemistry .
20363910
Among 731 colorectal cancers in two prospective cohort studies , 142 ( 19 % ) Cancertumors showed HIF1A overexpression , and 322 ( 46 % ) showed EPAS1 overexpression by immunohistochemistry .
20363910
HIF1A overexpression was significantly associated with Cancerhigher colorectal cancer specific mortality in Kaplan-Meier analysis ( log-rank test , P < 0.0001 ) , univariate Cox regression ( hazard ratio = 1.84 ; 95 % confidence interval , 1.37 to 2.47 ; P < 0.0001 ) and multivariate analysis ( adjusted hazard ratio = 1.72 ; 95 % confidence interval , 1.26 to 2.36 ; P = 0.0007 ) that adjusted for clinical and tumoral features , including microsatellite instability , TP53 ( p53 ) , PTGS2 ( cyclooxygenase-2 ) , CpG island methylator phenotype , and KRAS , BRAF , PIK3CA , and LINE-1 methylation .
20363910
HIF1A overexpression was significantly associated with higher colorectal cancer specific AdverseOutcomemortality in Kaplan-Meier analysis ( log-rank test , P < 0.0001 ) , univariate Cox regression ( hazard ratio = 1.84 ; 95 % confidence interval , 1.37 to 2.47 ; P < 0.0001 ) and multivariate analysis ( adjusted hazard ratio = 1.72 ; 95 % confidence interval , 1.26 to 2.36 ; P = 0.0007 ) that adjusted for clinical and tumoral features , including microsatellite instability , TP53 ( p53 ) , PTGS2 ( cyclooxygenase-2 ) , CpG island methylator phenotype , and KRAS , BRAF , PIK3CA , and LINE-1 methylation .
20363910
EPAS1 expression was inversely associated with Cancerhigh tumor grade ( P = 0.0017 ) and obesity ( body mass index > or = 30 kg/m2 ) ( P = 0.039 ) .
20363910
In conclusion , HIF1A expression is independently associated with AdverseOutcomepoor prognosis in colorectal cancer , suggesting HIF1A as a biomarker with potentially important therapeutic implications .
20363910
In conclusion , HIF1A expression is independently associated with poor prognosis in Cancercolorectal cancer , suggesting HIF1A as a biomarker with potentially important therapeutic implications .
20368538
PURPOSE : We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism ( SNP ) located in the same exon of the IDH1 gene in patients with cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) in the context of other prognostic markers .
20368568
PURPOSE : Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor ( VEGFR ) activity are critical in the pathogenesis of Cancermedullary thyroid cancer ( MTC ) .
20368568
Secondary end points included Diseasetoxicity assessment and response correlation with tumor markers , functional imaging , and RET mutations .
20368568
Secondary end points included toxicity assessment and response correlation with Cancertumor markers , functional imaging , and RET mutations .
20368568
RESULTS : Of 16 patients treated in arm B , one achieved partial response ( PR ; 6.3 % ; 95 % CI , 0.2 % to 30.2 % ) , 14 had Diseasestable disease ( SD ; 87.5 % ; 95 % CI , 61.7 % to 99.5 % ) , and one was nonevaluable .
20368568
In a post hoc analysis of 10 arm B patients with Diseaseprogressive disease ( PD ) before study , one patient had PR of 21+ months , four patients had SD > or = 15 months , four patients had SD < or = 6 months , and one patient had clinical PD .
20368568
CancerTumor markers decreased in the majority of patients , and RET mutations were detected in 10 of 12 sporadic MTCs analyzed .
20368568
Caution should be taken because of the rare but Diseasefatal toxicity potentially associated with sorafenib .
20376086
Recent whole-genome sequencing efforts led to the identification of IDH1 ( R132 ) mutations in Canceracute myeloid leukemia ( AML ) patients .
20421455
Mutations in the nicotinamide adenine dinucleotide phosphate ( + )-dependent isocitrate dehydrogenase gene 2 ( IDH2 ) have recently been found in patients with Canceracute myeloid leukemia ( AML ) as well as in patients with leukemic transformation of myeloproliferative neoplasms .
20445578
Relapse is the most common cause of treatment failure in Cancerpediatric acute lymphoblastic leukemia ( ALL ) and is often difficult to predict .
20445578
Consequently , IKZF1 deletion status allowed the prospective identification of 53 % of the relapse-prone NHR classified patients within this subgroup and , therefore , serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for AdverseOutcomefuture risk stratification .
20453058
PURPOSE : The class I phosphatidylinositol 3 ' kinase ( PI3K ) plays a major role in proliferation and survival in a wide variety of Cancerhuman cancers .
20453058
EXPERIMENTAL DESIGN : We used a large panel of Cancerbreast cancer cell lines and in vivo xenograft models to identify candidate predictive biomarkers for a selective inhibitor of class I PI3K that is currently in clinical development .
20473330
A hallmark of Cancercancer is the deregulation of cell-cycle machinery , ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression .
20473330
A hallmark of cancer is the deregulation of cell-cycle machinery , ultimately facilitating aberrant proliferation that fuels tumorigenesis and Diseasedisease progression .
20473330
Particularly , in Cancerbreast cancers , cyclin D1 has a crucial role in the development of disease .
20473330
Particularly , in breast cancers , cyclin D1 has a crucial role in the development of Diseasedisease .
20473330
Recently , a highly specific inhibitor of CDK4/6 activity ( PD-0332991 ) has been developed that may have efficacy in the treatment of Cancerbreast cancer .
20473330
To interrogate the utility of PD-0332991 in treating Cancerbreast cancers , therapeutic response was evaluated on a panel of breast cancer cell lines .
20473330
To interrogate the utility of PD-0332991 in treating breast cancers , therapeutic response was evaluated on a panel of Cancerbreast cancer cell lines .
20473330
However , to interrogate the functional consequence of Rb directly , knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of Cancerbreast cancer .
20494930
BACKGROUND : DiseaseMyelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia .
20494930
BACKGROUND : Myelodysplastic syndromes are a heterogeneous group of Diseasehematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia .
20494930
BACKGROUND : Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into Canceracute myeloid leukemia .
20494930
Heterozygous missense mutations in IDH1 at position R132 and in IDH2 at positions R140 and R172 have recently been reported in Canceracute myeloid leukemia .
20494930
However , little is known about the incidence and prognostic impact of IDH1 and IDH2 mutations in Diseasemyelodysplastic syndromes .
20494930
DESIGN AND METHODS : We examined 193 patients with Diseasemyelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 ( R132 ) , IDH2 ( R172 and R140 ) , and NPM1 by direct sequencing .
20494930
DESIGN AND METHODS : We examined 193 patients with myelodysplastic syndromes and 53 patients with Canceracute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 ( R132 ) , IDH2 ( R172 and R140 ) , and NPM1 by direct sequencing .
20494930
DESIGN AND METHODS : We examined 193 patients with myelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from Diseasemyelodysplastic syndromes for mutations in IDH1 ( R132 ) , IDH2 ( R172 and R140 ) , and NPM1 by direct sequencing .
20494930
RESULTS : We found that mutations in IDH1 occurred with a frequency of 3.6 % in Diseasemyelodysplastic syndromes ( 7 mutations in 193 patients ) and 7.5 % in acute myeloid leukemia following myelodysplastic syndromes ( 4 mutations in 53 patients ) .
20494930
RESULTS : We found that mutations in IDH1 occurred with a frequency of 3.6 % in myelodysplastic syndromes ( 7 mutations in 193 patients ) and 7.5 % in Canceracute myeloid leukemia following myelodysplastic syndromes ( 4 mutations in 53 patients ) .
20494930
RESULTS : We found that mutations in IDH1 occurred with a frequency of 3.6 % in myelodysplastic syndromes ( 7 mutations in 193 patients ) and 7.5 % in acute myeloid leukemia following Diseasemyelodysplastic syndromes ( 4 mutations in 53 patients ) .
20494930
Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with Canceracute myeloid leukemia following myelodysplastic syndromes ( 7.5 % ) .
20494930
Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following Diseasemyelodysplastic syndromes ( 7.5 % ) .
20494930
No IDH2 R140 or R172 mutations were identified in patients with Diseasemyelodysplastic syndromes .
20494930
The presence of IDH1 mutations was associated with a shorter overall survival ( HR 3.20 ; 95 % CI 1.47-6 .99 ) and a higher rate of transformation into Canceracute myeloid leukemia ( 67 % versus 28 % , P = 0.04 ) .
20494930
In multivariate analysis when considering karyotype , transfusion dependence and International Prognostic Scoring System score , IDH1 mutations remained an independent prognostic marker in Diseasemyelodysplastic syndromes ( HR 3.57 ; 95 % CI 1.59-8 .02 ; P = 0.002 ) .
20494930
CONCLUSIONS : These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with Diseasemyelodysplastic syndromes , and may become useful as a poor risk marker in these patients .
20494930
CONCLUSIONS : These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes , and may become useful as a AdverseOutcomepoor risk marker in these patients .
20522446
Recently , two small-molecule kinase inhibitors targeting epidermal growth factor receptor have proven effective in the treatment of Cancernon small cell lung cancer .
20522446
We reported a case of Cancernon small cell lung cancer harboring a rare epidermal growth factor somatic mutation , codon 768 AGC > ATC in exon 20 ( S768I ) , who showed a good clinical response to gefitinib .
20530316
BACKGROUND : CancerOropharyngeal squamous-cell carcinomas caused by human papillomavirus ( HPV ) are associated with favorable survival , but the independent prognostic significance of tumor HPV status remains unknown .
20530316
BACKGROUND : Oropharyngeal squamous-cell carcinomas caused by human papillomavirus ( HPV ) are associated with favorable survival , but the independent prognostic significance of Cancertumor HPV status remains unknown .
20530316
METHODS : We performed a retrospective analysis of the association between Cancertumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated fractionation radiotherapy ( with acceleration by means of concomitant boost radiotherapy ) with standard fractionation radiotherapy , each combined with cisplatin therapy , in patients with squamous-cell carcinoma of the head and neck .
20530316
METHODS : We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV Canceroropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated fractionation radiotherapy ( with acceleration by means of concomitant boost radiotherapy ) with standard fractionation radiotherapy , each combined with cisplatin therapy , in patients with squamous-cell carcinoma of the head and neck .
20530316
METHODS : We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated fractionation radiotherapy ( with acceleration by means of concomitant boost radiotherapy ) with standard fractionation radiotherapy , each combined with cisplatin therapy , in patients with Cancersquamous-cell carcinoma of the head and neck .
20530316
Proportional-hazards models were used to compare the AdverseOutcomerisk of death among patients with HPV positive cancer and those with HPV negative cancer .
20530316
Proportional-hazards models were used to compare the risk of death among patients with CancerHPV positive cancer and those with HPV negative cancer .
20530316
Proportional-hazards models were used to compare the risk of death among patients with HPV positive cancer and those with CancerHPV negative cancer .
20530316
A total of 63.8 % of patients with Canceroropharyngeal cancer ( 206 of 323 ) had HPV positive tumors ; these patients had better 3-year rates of overall survival ( 82.4 % , vs. 57.1 % among patients with HPV negative tumors ; P < 0.001 by the log-rank test ) and , after adjustment for age , race , tumor and nodal stage , tobacco exposure , and treatment assignment , had a 58 % reduction in the risk of death ( hazard ratio , 0.42 ; 95 % CI , 0.27 to 0.66 ) .
20530316
A total of 63.8 % of patients with oropharyngeal cancer ( 206 of 323 ) had CancerHPV positive tumors ; these patients had better 3-year rates of overall survival ( 82.4 % , vs. 57.1 % among patients with HPV negative tumors ; P < 0.001 by the log-rank test ) and , after adjustment for age , race , tumor and nodal stage , tobacco exposure , and treatment assignment , had a 58 % reduction in the risk of death ( hazard ratio , 0.42 ; 95 % CI , 0.27 to 0.66 ) .
20530316
A total of 63.8 % of patients with oropharyngeal cancer ( 206 of 323 ) had HPV positive tumors ; these patients had better 3-year rates of overall survival ( 82.4 % , vs. 57.1 % among patients with CancerHPV negative tumors ; P < 0.001 by the log-rank test ) and , after adjustment for age , race , tumor and nodal stage , tobacco exposure , and treatment assignment , had a 58 % reduction in the risk of death ( hazard ratio , 0.42 ; 95 % CI , 0.27 to 0.66 ) .
20530316
A total of 63.8 % of patients with oropharyngeal cancer ( 206 of 323 ) had HPV positive tumors ; these patients had better 3-year rates of overall survival ( 82.4 % , vs. 57.1 % among patients with HPV negative tumors ; P < 0.001 by the log-rank test ) and , after adjustment for age , race , Cancertumor and nodal stage , tobacco exposure , and treatment assignment , had a 58 % reduction in the risk of death ( hazard ratio , 0.42 ; 95 % CI , 0.27 to 0.66 ) .
20530316
A total of 63.8 % of patients with oropharyngeal cancer ( 206 of 323 ) had HPV positive tumors ; these patients had better 3-year rates of overall survival ( 82.4 % , vs. 57.1 % among patients with HPV negative tumors ; P < 0.001 by the log-rank test ) and , after adjustment for age , race , tumor and nodal stage , tobacco exposure , and treatment assignment , had a 58 % reduction in the AdverseOutcomerisk of death ( hazard ratio , 0.42 ; 95 % CI , 0.27 to 0.66 ) .
20530316
The AdverseOutcomerisk of death significantly increased with each additional pack-year of tobacco smoking .
20530316
Using recursive partitioning analysis , we classified our patients as having a low , intermediate , or AdverseOutcomehigh risk of death on the basis of four factors : HPV status , pack-years of tobacco smoking , tumor stage , and nodal stage .
20530316
Using recursive partitioning analysis , we classified our patients as having a low , intermediate , or high risk of death on the basis of four factors : HPV status , pack-years of tobacco smoking , Cancertumor stage , and nodal stage .
20530316
CONCLUSIONS : CancerTumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer .
20530316
CONCLUSIONS : Tumor HPV status is a strong and independent prognostic factor for survival among patients with Canceroropharyngeal cancer .
20537386
CancerChronic Myeloid Leukemia ( CML ) is a clonal disease characterized by the presence of the Philadelphia ( Ph+ ) chromosome and its oncogenic product , BCR-ABL , a constitutively active tyrosine kinase , that is present in > 90 % of the patients .
20537386
Chronic Myeloid Leukemia ( CML ) is a Diseaseclonal disease characterized by the presence of the Philadelphia ( Ph+ ) chromosome and its oncogenic product , BCR-ABL , a constitutively active tyrosine kinase , that is present in > 90 % of the patients .
20537386
Epidemiologic data indicates that almost 5000 new cases are reported every year and 10 % of these patients eventually succumb to the Diseasedisease .
20537386
However , the complete eradication of CML in patients receiving imatinib was limited by the emergence of resistance mostly due to mutations in the ABL kinase domain and to a lesser extent by Diseasemolecular residual disease after treatment .
20538800
Somatic mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) were recently demonstrated in Canceracute myeloid leukemia ( AML ) , but their prevalence and prognostic impact remain to be explored in large extensively characterized AML series , and also in various other hematologic malignancies .
20538800
Somatic mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) were recently demonstrated in acute myeloid leukemia ( AML ) , but their prevalence and prognostic impact remain to be explored in large extensively characterized AML series , and also in Cancervarious other hematologic malignancies .
20538800
Moreover , we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias ( n = 96 ) , a single case of Canceracute lymphoblastic leukemia ( n = 96 ) , and none in chronic myeloid leukemias ( n = 81 ) .
20538800
Moreover , we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias ( n = 96 ) , a single case of acute lymphoblastic leukemia ( n = 96 ) , and none in Cancerchronic myeloid leukemias ( n = 81 ) .
20542753
CancerBladder cancer accounts for nearly 5 % of all newly diagnosed cancers in Jordan , with a much higher frequency in males .
20542753
Bladder cancer accounts for nearly 5 % of all newly diagnosed Cancercancers in Jordan , with a much higher frequency in males .
20542753
Recent studies have shown that activating mutations in FGFR3 are the most common findings in Cancernon invasive low grade bladder tumors .
20542753
In this study , we , retrospectively , investigated a cohort of 121 Cancerbladder cancer patients with various grades and stages of the tumor for molecular changes in FGFR3 .
20542753
In this study , we , retrospectively , investigated a cohort of 121 bladder cancer patients with various grades and stages of the Cancertumor for molecular changes in FGFR3 .
20542753
Our results indicate that both mutations and overexpression of FGFR3 are correlated together , and are more prevalent in early stage ( pTa and pT1 ) and low grade ( G1 and G2 ) Cancerbladder tumors .
20542753
Multivariate Cox proportional hazards model analysis of overall survival for the following variables : age , gender , stage and grade of Cancertumor , and FGFR3 ( expression and mutation ) revealed that age , stage and grade of tumor are independent predictors of overall survival in patients with bladder cancer .
20542753
Multivariate Cox proportional hazards model analysis of overall survival for the following variables : age , gender , stage and grade of tumor , and FGFR3 ( expression and mutation ) revealed that age , stage and grade of Cancertumor are independent predictors of overall survival in patients with bladder cancer .
20542753
Multivariate Cox proportional hazards model analysis of overall survival for the following variables : age , gender , stage and grade of tumor , and FGFR3 ( expression and mutation ) revealed that age , stage and grade of tumor are independent predictors of overall survival in patients with Cancerbladder cancer .
20542753
Our work is the first to address the molecular status of FGFR3 in Jordanian patients with Cancerbladder cancer , and provides further support for FGFR3 as a key player in the initiation of bladder tumors .
20542753
Our work is the first to address the molecular status of FGFR3 in Jordanian patients with bladder cancer , and provides further support for FGFR3 as a key player in the initiation of Cancerbladder tumors .
20570890
Mutations in RAS proteins occur widely in Cancerhuman cancer .
20570890
We performed a multiplatform genomic analysis to characterize , in a nonbiased manner , the biological , biochemical , and prognostic significance of Ras pathway alterations in Cancercolorectal tumors and other solid tumor malignancies .
20570890
We performed a multiplatform genomic analysis to characterize , in a nonbiased manner , the biological , biochemical , and prognostic significance of Ras pathway alterations in colorectal tumors and Cancerother solid tumor malignancies .
20570890
Mutations in exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with Cancercolorectal cancer .
20570890
These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number , in Cancerhuman tumors and tumor cell lines .
20570890
These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number , in human tumors and Cancertumor cell lines .
20570890
Our findings suggest that RAS mutation is not a binary variable in Cancertumors , and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients .
20570890
Our findings suggest that RAS mutation is not a binary variable in tumors , and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in Cancercancer patients .
20601954
In Diseasemyelodysplastic syndromes ( MDS ) , deletions of chromosome 7 or 7q are common and correlate with a poor prognosis .
20601954
In myelodysplastic syndromes ( MDS ) , deletions of chromosome 7 or 7q are common and correlate with a AdverseOutcomepoor prognosis .
20609353
We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a Cancermouse tumor model that closely recapitulates human non small cell lung carcinoma ( NSCLC ) .
20609353
We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates Cancerhuman non small cell lung carcinoma ( NSCLC ) .
20609353
More importantly , targeting Cdk4 alleles in Canceradvanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression .
20609353
More importantly , targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents Cancertumor progression .
20619739
BACKGROUND : Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor ( EGFR ) antibodies , the Cancertumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab .
20619739
BACKGROUND : Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor ( EGFR ) antibodies , the tumours of patients with Cancermetastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab .
20619739
However , most patients with CancerKRAS wild-type tumours still do not respond .
20619739
We studied the effect of other downstream mutations on the efficacy of cetuximab in , to our knowledge , the largest cohort to date of patients with Cancerchemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era .
20619739
METHODS : 1022 Cancertumour DNA samples ( 73 from fresh-frozen and 949 from formalin fixed , paraffin embedded tissue ) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries .
20619739
773 Cancerprimary tumour samples had sufficient quality DNA and were included in mutation frequency analyses ; mass spectrometry genotyping of tumour samples for KRAS , BRAF , NRAS , and PIK3CA was done centrally .
20619739
773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses ; mass spectrometry genotyping of Cancertumour samples for KRAS , BRAF , NRAS , and PIK3CA was done centrally .
20619739
FINDINGS : 40.0 % ( 299/747 ) of the Cancertumours harboured a KRAS mutation , 14.5 % ( 108/743 ) harboured a PIK3CA mutation ( of which 68.5 % [ 74/108 ] were located in exon 9 and 20.4 % [ 22/108 ] in exon 20 ) , 4.7 % ( 36/761 ) harboured a BRAF mutation , and 2.6 % ( 17/644 ) harboured an NRAS mutation .
20628391
BACKGROUND : The impact of thymidylate synthase ( TYMS ) and UDP-glucoronosyltransferase 1A ( UGT1A ) germline polymorphisms on the outcome of Cancercolorectal cancer ( CRC ) patients treated with irinotecan plus 5-fluorouracil ( irinotecan/5FU ) is still controversial .
20628391
Their association with response , Diseasetoxicity and survival was investigated by univariate and multivariate statistical analysis .
20628391
RESULTS : TYMS 3TRP/3TRP genotype was the only independent predictor of Cancertumour response ( OR = 5.87 , 95 % confidence interval ( CI ) = 1.68-20 .45 ; P = 0.005 ) .
20628391
UGT1A1 ( * ) 28/( * ) 28 was predictive for Diseasehaematologic toxicity ( OR = 6.27 , 95 % CI = 1.09-36 .12 ; P = 0.04 ) , specifically for neutropenia alone ( OR = 6.40 , 95 % CI = 1.11-37 .03 ; P = 0.038 ) or together with diarrhoea ( OR = 18.87 , 95 % CI = 2.14-166 .67 ; P = 0.008 ) .
20628391
UGT1A1 ( * ) 28/( * ) 28 was predictive for haematologic toxicity ( OR = 6.27 , 95 % CI = 1.09-36 .12 ; P = 0.04 ) , specifically for Diseaseneutropenia alone ( OR = 6.40 , 95 % CI = 1.11-37 .03 ; P = 0.038 ) or together with diarrhoea ( OR = 18.87 , 95 % CI = 2.14-166 .67 ; P = 0.008 ) .
20628391
UGT1A9 ( * ) 1/( * ) 1 was associated with Diseasenon haematologic toxicity ( OR = 2.70 , 95 % CI = 1.07-6 .82 ; P = 0.035 ) .
20628391
Haplotype VII ( all non favourable alleles ) was associated with Diseasenon haematologic toxicity ( OR = 2.11 , 95 % CI = 1.12-3 .98 ; P = 0.02 ) .
20628391
CONCLUSION : TYMS and UGT1A polymorphisms influence on Cancertumour response and toxicities derived from irinotecan/5FU treatment in CRC patients .
20628391
CONCLUSION : TYMS and UGT1A polymorphisms influence on tumour response and Diseasetoxicities derived from irinotecan/5FU treatment in CRC patients .
20651371
A panel of 11 genes selected according to microarray analysis were validated and tested further in 11 Cancercancer cell lines , resulting in 4 genes , CXCR4 , CDK6 , USP15 and CDH1 .
20651371
Histoculture drug response assay ( HDRA ) was used to examine docetaxel sensitivity , while qRT-PCR was used to measure the mRNA levels of the genes in 25 surgically dissected Cancergastric cancer specimens .
20651371
RESULTS : Only CXCR4 mRNA levels in Cancergastric cancer tissues were correlated with docetaxel sensitivity ( R ( 2 ) = 0.23 , p = 0.019 ) and significantly higher in resistant specimens ( p = 0.038 ) .
20651371
CONCLUSION : CXCR4 mRNA expression levels may be a potential predictive biomarker in Cancergastric cancer .
20693978
CancerGranulosa cell tumors of the ovary represent ~ 5 % of malignant ovarian cancers .
20693978
Granulosa cell tumors of the ovary represent ~ 5 % of Cancermalignant ovarian cancers .
20693978
It has recently been reported that 95-97 % of Canceradult granulosa cell tumors carry a unique somatic mutation in the FOXL2 gene .
20693978
We undertook this study to verify the presence of the FOXL2 Cys134Trp mutation in two geographically independent cohorts of Cancergranulosa cell tumors and to examine the expression pattern of FOXL2 in these tumors .
20693978
We undertook this study to verify the presence of the FOXL2 Cys134Trp mutation in two geographically independent cohorts of granulosa cell tumors and to examine the expression pattern of FOXL2 in these Cancertumors .
20693978
A total of 56 Cancertumors with the histological diagnosis of adult granulosa cell tumor from two centers , Melbourne and Helsinki , were examined for the presence of the mutation using direct sequence analysis .
20693978
A total of 56 tumors with the histological diagnosis of Canceradult granulosa cell tumor from two centers , Melbourne and Helsinki , were examined for the presence of the mutation using direct sequence analysis .
20693978
Two Cancergranulosa cell tumor derived cell lines , COV434 and KGN , three juvenile granulosa cell tumors and control tissues were also examined .
20693978
Two granulosa cell tumor derived cell lines , COV434 and KGN , three Cancerjuvenile granulosa cell tumors and control tissues were also examined .
20693978
We found that 52 of the 56 Canceradult granulosa cell tumors harbor the mutation , of which three were hemi and homozygous .
20693978
The expression levels of FOXL2 were similar across the Canceradult granulosa cell tumors and the normal ovary controls ; one mutation negative granulosa cell tumor had high FOXL2 mRNA levels , whereas the COV434 cells and two of the three juvenile granulosa cell tumors lacked the expression of FOXL2 .
20693978
The expression levels of FOXL2 were similar across the adult granulosa cell tumors and the normal ovary controls ; one Cancermutation negative granulosa cell tumor had high FOXL2 mRNA levels , whereas the COV434 cells and two of the three juvenile granulosa cell tumors lacked the expression of FOXL2 .
20693978
The expression levels of FOXL2 were similar across the adult granulosa cell tumors and the normal ovary controls ; one mutation negative granulosa cell tumor had high FOXL2 mRNA levels , whereas the COV434 cells and two of the three Cancerjuvenile granulosa cell tumors lacked the expression of FOXL2 .
20693978
Our data provide confirmation of the frequent presence of the FOXL2 C134W mutation in Canceradult granulosa cell tumors and demonstrate that the mutation is not associated with altered FOXL2 expression .
20693978
The mutation analysis may be a useful tool to differentiate particularly between Cancercell rich diffuse granulosa cell tumors and mitotically active sex cord-stromal tumors .
20693978
The mutation analysis may be a useful tool to differentiate particularly between cell rich diffuse granulosa cell tumors and mitotically Canceractive sex cord-stromal tumors .
20693978
This unique FOXL2 mutation appears to be characteristic of Canceradult granulosa cell tumors .
20696054
BACKGROUND : CancerAdenocarcinomas of the tongue are rare and represent the minority ( 20 to 25 % ) of salivary gland tumors affecting the tongue .
20696054
BACKGROUND : Adenocarcinomas of the tongue are rare and represent the minority ( 20 to 25 % ) of Cancersalivary gland tumors affecting the tongue .
20696054
We investigated the utility of massively parallel sequencing to characterize an Canceradenocarcinoma of the tongue , before and after treatment .
20696054
RESULTS : In the Cancerpre-treatment tumor we identified 7,629 genes within regions of copy number gain .
20696054
There were 1,078 genes that exhibited increased expression relative to the blood and Cancerunrelated tumors and four genes contained somatic protein coding mutations .
20696054
Our analysis suggested the Cancertumor cells were driven by the RET oncogene .
20696054
Consistent with our observations , administration of sunitinib was associated with Diseasestable disease lasting 4 months , after which the lung lesions began to grow .
20696054
Administration of sorafenib and sulindac provided Diseasedisease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared .
20696054
Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the Cancercancer progressed and new lesions appeared .
20696054
A recurring Cancermetastasis possessed 7,288 genes within copy number amplicons , 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations .
20696054
A recurring metastasis possessed 7,288 genes within copy number amplicons , 385 genes exhibiting increased expression relative to Cancerother tumors and 9 new somatic protein coding mutations .
20696054
CONCLUSIONS : We conclude that complete genomic characterization of a Cancerrare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist .
20696054
These results also provide direct in vivo genomic evidence for mutational evolution within a Cancertumor under drug selection and potential mechanisms of drug resistance accrual .
20697090
PURPOSE : The precise prognostic impact of TP53 mutation and its incorporation into treatment algorithms in Cancerchronic lymphocytic leukemia ( CLL ) is unclear .
20697090
CONCLUSION : CLL with TP53 mutation carries a AdverseOutcomepoor prognosis regardless of the presence of 17p deletion when treated with F based chemotherapy .
20728210
BACKGROUND : Trastuzumab , a monoclonal antibody against human epidermal growth factor receptor 2 ( HER2 ; also known as ERBB2 ) , was investigated in combination with chemotherapy for first-line treatment of HER2 positive advanced gastric or Cancergastro-oesophageal junction cancer .
20728210
Patients with gastric or Cancergastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation .
20728210
Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their Cancertumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation .
20728210
Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of Diseasedisease , primary cancer site , and measurability of disease , implemented with a central interactive voice recognition system .
20728210
Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of disease , Cancerprimary cancer site , and measurability of disease , implemented with a central interactive voice recognition system .
20728210
Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status , chemotherapy regimen , extent of disease , primary cancer site , and measurability of Diseasedisease , implemented with a central interactive voice recognition system .
20728210
The most common adverse events in both groups were nausea ( trastuzumab plus chemotherapy , 197 [ 67 % ] vs chemotherapy alone , 184 [ 63 % ] ) , vomiting ( 147 [ 50 % ] vs 134 [ 46 % ] ) , and Diseaseneutropenia ( 157 [ 53 % ] vs 165 [ 57 % ] ) .
20728210
INTERPRETATION : Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2 positive advanced gastric or Cancergastro-oesophageal junction cancer .
20733134
PURPOSE : Mutations leading to constitutive activation of the FMS like tyrosine kinase 3 receptor ( FLT3 ) occur in blasts of 30 % of patients with Canceracute myeloid leukemia ( AML ) .
20733134
Midostaurin ( PKC412 ; N-benzoylstaurosporin ) is a multitargeted tyrosine kinase inhibitor , with demonstrated activity in patients with AML and Diseasemyelodysplastic syndrome ( MDS ) with FLT3 mutations .
20733134
The drug was discontinued in the absence of response at 2 months , Diseasedisease progression , or unacceptable toxicity .
20733134
The drug was discontinued in the absence of response at 2 months , disease progression , or Diseaseunacceptable toxicity .
20733134
Both doses were well tolerated ; there were no differences in Diseasetoxicity or response rate according to the dose of midostaurin .
20739657
The Ataxia Telangiectasia Mutated ( ATM ) gene is frequently inactivated in Cancerlymphoid malignancies such as chronic lymphocytic leukemia ( CLL ) , T-prolymphocytic leukemia ( T-PLL ) , and mantle cell lymphoma ( MCL ) and is associated with defective apoptosis in response to alkylating agents and purine analogues .
20739657
The Ataxia Telangiectasia Mutated ( ATM ) gene is frequently inactivated in lymphoid malignancies such as Cancerchronic lymphocytic leukemia ( CLL ) , T-prolymphocytic leukemia ( T-PLL ) , and mantle cell lymphoma ( MCL ) and is associated with defective apoptosis in response to alkylating agents and purine analogues .
20739657
The Ataxia Telangiectasia Mutated ( ATM ) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia ( CLL ) , CancerT-prolymphocytic leukemia ( T-PLL ) , and mantle cell lymphoma ( MCL ) and is associated with defective apoptosis in response to alkylating agents and purine analogues .
20739657
The Ataxia Telangiectasia Mutated ( ATM ) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia ( CLL ) , T-prolymphocytic leukemia ( T-PLL ) , and Cancermantle cell lymphoma ( MCL ) and is associated with defective apoptosis in response to alkylating agents and purine analogues .
20739657
Poly ( ADP-ribose ) polymerase ( PARP ) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize CancerATM deficient tumor cells to killing .
20739657
A nonobese diabetic and severe combined immunodeficient ( NOD and SCID ) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced Cancertumor load and an increased survival of animals after olaparib treatment in vivo .
20739657
Addition of olaparib sensitized CancerATM null tumor cells to DNA damaging agents .
20739657
We suggest that olaparib would be an appropriate agent for treating Cancerrefractory ATM mutant lymphoid tumors .
20805365
Mutations in the IDH1 gene at position R132 coding for the enzyme cytosolic isocitrate dehydrogenase are known in Cancerglioma and have recently been detected also in acute myeloid leukemia ( AML ) .
20805365
Mutations in the IDH1 gene at position R132 coding for the enzyme cytosolic isocitrate dehydrogenase are known in glioma and have recently been detected also in Canceracute myeloid leukemia ( AML ) .
20805365
We detected IDH1R132 mutations in 93 of 1414 patients ( 6.6 % ) with a clear prevalence in AdverseOutcomeintermediate risk karyotype group ( 10.4 % , P < .001 ) .
20805365
Prognosis was adversely affected by IDH1 mutations with trend for shorter overall survival ( P = .110 ) , a shorter event-free survival ( P < .003 ) and a higher AdverseOutcomecumulative risk for relapse ( P = .001 ) .
20813970
Phosphatase and tensin homolog ( PTEN ) is a key modulator of trastuzumab sensitivity in HER2 overexpressing Cancerbreast cancer .
20813970
CancerPrimary tumor tissue was available from 137 patients with HER2 overexpressing metastatic breast cancer who had received trastuzumab based chemotherapy .
20813970
Primary tumor tissue was available from 137 patients with HER2 overexpressing Cancermetastatic breast cancer who had received trastuzumab based chemotherapy .
20813970
PTEN loss was significantly associated with a poor response to trastuzumab ( P = 0.028 ) and shorter survival time ( P = 0.008 ) in patients who had received first-line trastuzumab and in patients with estrogen receptor- ( P = 0.029 ) and Cancerprogesterone receptor negative tumors ( P = 0.033 ) .
20813970
Our findings may facilitate the evaluation of Cancertumor response to trastuzumab based and targeted therapies .
20818844
BACKGROUND : The identification of somatic mutations in the gene encoding the serine threonine protein kinase B-RAF ( BRAF ) in the majority of Cancermelanomas offers an opportunity to test oncogene targeted therapy for this disease .
20818844
BACKGROUND : The identification of somatic mutations in the gene encoding the serine threonine protein kinase B-RAF ( BRAF ) in the majority of melanomas offers an opportunity to test oncogene targeted therapy for this Diseasedisease .
20818844
Patients received PLX4032 twice daily until they had Diseasedisease progression .
20818844
Pharmacokinetic analysis and Cancertumor response assessments were conducted in all patients .
20818844
In selected patients , Cancertumor biopsy was performed before and during treatment to validate BRAF inhibition .
20818844
RESULTS : A total of 55 patients ( 49 of whom had Cancermelanoma ) were enrolled in the dose escalation phase , and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase .
20818844
RESULTS : A total of 55 patients ( 49 of whom had melanoma ) were enrolled in the dose escalation phase , and 32 additional patients with Cancermetastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase .
20818844
In the dose escalation cohort , among the 16 patients with Cancermelanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily , 10 had a partial response and 1 had a complete response .
20818844
In the dose escalation cohort , among the 16 patients with melanoma whose Cancertumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily , 10 had a partial response and 1 had a complete response .
20818844
CONCLUSIONS : Treatment of Cancermetastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients .
20818844
CONCLUSIONS : Treatment of metastatic melanoma with PLX4032 in patients with Cancertumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients .
20818844
CONCLUSIONS : Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or Cancerpartial tumor regression in the majority of patients .
20826716
INTRODUCTION : We conducted a systematic review and meta-analysis to assess epidermal growth factor receptor ( EGFR ) gene copy number as a potential biomarker of survival for patients with Canceradvanced non-small-cell lung cancer ( NSCLC ) receiving single-agent treatment with EGFR tyrosine kinase inhibitors ( TKIs ) .
20840671
AIMS : The epidermal growth factor receptor ( EGFR ) is a tyrosine kinase ( TK ) involved in the Cancertumour progression of many cancer types and may serve as an important therapeutic target ( erlotinib , cetuximab ) .
20840671
AIMS : The epidermal growth factor receptor ( EGFR ) is a tyrosine kinase ( TK ) involved in the tumour progression of Cancermany cancer types and may serve as an important therapeutic target ( erlotinib , cetuximab ) .
20840671
The aim of this study was performed to determine the potential impact of Cancertumour heterogeneity on anti-EGFR therapy in Barrett 's adenocarcinoma ( BAC ) .
20840671
The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti-EGFR therapy in Barrett 's Canceradenocarcinoma ( BAC ) .
20840671
A subset of 20 samples was also sequenced for EGFR exons 18-21 and CancerKirsten rat sarcoma viral oncogene homologue ( KRAS ) exons 2-3 mutations .
20840671
EGFR amplification was seen in seven ( 6.25 % ) of 112 interpretable BAC and typically high-level with more than 10-20 EGFR copies per Cancertumour cell ( EGFR and centromere 7 ratio > 3 ) .
20840671
EGFR amplification was associated with high pT , pN and AdverseOutcomepoor prognosis ( P = 0.0004 ) .
20840671
Identical EGFR amplification status was found in 29 Cancerprimary tumours and 29 matched lymph node metastases .
20840671
CONCLUSION : The high level and homogeneity of EGFR amplification in Cancerprimary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC .
20871596
Recurrent translocation of BRD4 is observed in a genetically defined , incurable subtype of Cancerhuman squamous carcinoma .
20940188
We studied the activity of IPI-504 after epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) therapy in patients with advanced , molecularly defined Cancernon-small-cell lung cancer ( NSCLC ) .
20940188
PATIENTS AND METHODS : Patients with advanced NSCLC , prior treatment with EGFR TKIs , and Cancertumor tissue available for molecular genotyping were enrolled in this prospective , nonrandomized , multicenter , phase II study of IPI-504 monotherapy .
20940188
RESULTS : Seventy-six patients were enrolled between December 2007 and May 2009 from 10 CancerUnited States cancer centers .
20940188
Although both EGFR groups were below the target ORR of 20 % , among the three patients with an ALK gene rearrangement , two had partial responses and the third had prolonged Diseasestable disease ( 7.2 months , 24 % reduction in tumor size ) .
20940188
Although both EGFR groups were below the target ORR of 20 % , among the three patients with an ALK gene rearrangement , two had partial responses and the third had prolonged stable disease ( 7.2 months , 24 % reduction in Cancertumor size ) .
20956938
KRAS mutation is a predictive biomarker for resistance to cetuximab ( Erbitux ) in Cancermetastatic colorectal cancer ( mCRC ) .
20956938
Next , we analyzed Cancertumor growth with cetuximab , dasatinib or their combination in vivo .
20956938
CancerKRAS mutant tumors exhibited minimal response to dasatinib monotherapy .
20956938
The data presented in this study indicate that dasatinib can sensitize CancerKRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key signaling pathways .
20956938
Furthermore , these results suggest that signaling via EGFR and SFKs may be necessary for cell proliferation and survival of CancerKRAS mutant CRC tumors .
20975057
OBJECTIVES : Recent studies have shown that IDH1 and IDH2 mutations occur frequently in Cancergliomas , including low-grade gliomas .
20975057
OBJECTIVES : Recent studies have shown that IDH1 and IDH2 mutations occur frequently in gliomas , including Cancerlow-grade gliomas .
20975057
However , their impact on the prognosis and chemosensitivity of Cancerlow-grade gliomas remains unclear .
20975057
METHODS : Search for IDH1 and IDH2 mutations , loss of heterozygosity on chromosomes 1p and 19q , MGMT promoter methylation , and p53 expression was performed in a series of 271 Cancerlow-grade gliomas and correlated with overall survival .
20975057
Response to temozolomide was evaluated by progression-free survival , as well as by Cancertumor size on successive MRI scans , and then correlated with molecular alterations .
20975057
Further analysis of the course of the Diseasedisease prior to any treatment except for surgery ( untreated subgroup ) showed that 1p-19q codeletion was associated with prolonged progression-free survival in univariate analysis , whereas IDH mutation was not .
20975057
CONCLUSION : IDH mutation appears to be a significant marker of positive prognosis and chemosensitivity in Cancerlow-grade gliomas , independently of 1p-19q codeletion , whereas its impact on the course of untreated tumors seems to be limited .
20975057
CONCLUSION : IDH mutation appears to be a significant marker of positive prognosis and chemosensitivity in low-grade gliomas , independently of 1p-19q codeletion , whereas its impact on the course of Canceruntreated tumors seems to be limited .
20978259
CONTEXT : Patients with Cancermetastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13 mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab .
20978259
CONTEXT : Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13 mutated Cancertumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab .
20978259
DESIGN , SETTING , AND PATIENTS : We studied the association between KRAS mutation status ( p.G13D vs other KRAS mutations ) and response and survival in a pooled data set of 579 patients with Cancerchemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008 .
20978259
RESULTS : In comparison with patients with other KRAS mutated Cancertumors , patients with p.G13D-mutated tumors ( n = 32 ) treated with cetuximab had longer overall survival ( median , 7.6 [ 95 % confidence interval { CI } , 5.7-20 .5 ] months vs 5.7 [ 95 % CI , 4.9-6 .8 ] months ; adjusted hazard ratio [ HR ] , 0.50 ; 95 % CI , 0.31-0 .81 ; P = .005 ) and longer progression-free survival ( median , 4.0 [ 95 % CI , 1.9-6 .2 ] months vs 1.9 [ 95 % CI , 1.8-2 .8 ] months ; adjusted HR , 0.51 ; 95 % CI , 0.32-0 .81 ; P = .004 ) .
20978259
RESULTS : In comparison with patients with other KRAS mutated tumors , patients with Cancerp.G13D-mutated tumors ( n = 32 ) treated with cetuximab had longer overall survival ( median , 7.6 [ 95 % confidence interval { CI } , 5.7-20 .5 ] months vs 5.7 [ 95 % CI , 4.9-6 .8 ] months ; adjusted hazard ratio [ HR ] , 0.50 ; 95 % CI , 0.31-0 .81 ; P = .005 ) and longer progression-free survival ( median , 4.0 [ 95 % CI , 1.9-6 .2 ] months vs 1.9 [ 95 % CI , 1.8-2 .8 ] months ; adjusted HR , 0.51 ; 95 % CI , 0.32-0 .81 ; P = .004 ) .
20978259
CONCLUSIONS : In this analysis , use of cetuximab was associated with longer overall and progression-free survival among patients with Cancerchemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS mutated tumors .
20978259
CONCLUSIONS : In this analysis , use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with Cancerp.G13D-mutated tumors than with other KRAS mutated tumors .
20978259
CONCLUSIONS : In this analysis , use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS mutated Cancertumors .
20978259
Evaluation of cetuximab therapy in these Cancertumors in prospective randomized trials may be warranted .
20979469
BACKGROUND : Oncogenic fusion genes consisting of EML4 and Canceranaplastic lymphoma kinase ( ALK ) are present in a subgroup of non-small-cell lung cancers , representing 2 to 7 % of such tumors .
20979469
BACKGROUND : Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase ( ALK ) are present in a subgroup of Cancernon-small-cell lung cancers , representing 2 to 7 % of such tumors .
20979469
BACKGROUND : Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase ( ALK ) are present in a subgroup of non-small-cell lung cancers , representing 2 to 7 % of Cancersuch tumors .
20979469
We explored the therapeutic efficacy of inhibiting ALK in Cancersuch tumors in an early-phase clinical trial of crizotinib ( PF-02341066 ) , an orally available small-molecule inhibitor of the ALK tyrosine kinase .
20979469
METHODS : After screening Cancertumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements , we identified 82 patients with advanced ALK positive disease who were eligible for the clinical trial .
20979469
METHODS : After screening tumor samples from approximately 1500 patients with Cancernon-small-cell lung cancer for the presence of ALK rearrangements , we identified 82 patients with advanced ALK positive disease who were eligible for the clinical trial .
20979469
METHODS : After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements , we identified 82 patients with Diseaseadvanced ALK positive disease who were eligible for the clinical trial .
20979469
RESULTS : Patients with ALK rearrangements tended to be younger than those without the rearrangements , and most of the patients had little or no exposure to tobacco and had Canceradenocarcinomas .
20979469
At a mean treatment duration of 6.4 months , the overall response rate was 57 % ( 47 of 82 patients , with 46 confirmed partial responses and 1 confirmed complete response ) ; 27 patients ( 33 % ) had Diseasestable disease .
20979469
CONCLUSIONS : The inhibition of ALK in Cancerlung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients .
20979469
CONCLUSIONS : The inhibition of ALK in lung tumors with the ALK rearrangement resulted in Cancertumor shrinkage or stable disease in most patients .
20979469
CONCLUSIONS : The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or Diseasestable disease in most patients .
20979472
CancerInflammatory myofibroblastic tumor ( IMT ) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate .
20979472
Approximately half of IMTs carry rearrangements of the Canceranaplastic lymphoma kinase ( ALK ) locus on chromosome 2p23 , causing aberrant ALK expression .
20979472
These results support the dependence of ALK rearranged Cancertumors on ALK mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor .
20979472
These results support the dependence of ALK rearranged tumors on ALK mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this Cancersoft-tissue tumor .
20979473
The EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( Canceranaplastic lymphoma kinase ) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5 % of non-small-cell lung cancers , and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way .
20979473
The EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( anaplastic lymphoma kinase ) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5 % of Cancernon-small-cell lung cancers , and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way .
20979473
The EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( anaplastic lymphoma kinase ) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5 % of non-small-cell lung cancers , and clinical trials of specific inhibitors of ALK for the treatment of Cancersuch tumors are currently under way .
20979473
Here , we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in Cancertumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor .
20979473
Each mutation developed independently in subclones of the Cancertumor and conferred marked resistance to two different ALK inhibitors .
21030459
The ALK kinase inhibitor crizotinib ( PF-02341066 ) is clinically effective in patients with ALK translocated Cancercancers , but its efficacy will ultimately be limited by acquired drug resistance .
21030459
Here we report the identification of a secondary mutation in ALK , F1174L , as one cause of crizotinib resistance in a patient with an Cancerinflammatory myofibroblastic tumor ( IMT ) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy .
21030459
When present in cis with an ALK translocation , this mutation ( also detected in Cancerneuroblastomas ) causes an increase in ALK phosphorylation , cell growth , and downstream signaling .
21030459
Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK translocated Cancercancers .
21048039
BACKGROUND : The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil ( 5-FU ) significantly improved overall survival in the first-line treatment of patients with recurrent and/or Cancermetastatic squamous cell carcinoma of the head and neck ( R/M SCCHN ) compared with platinum/5-FU alone .
21048039
The aim of this investigation was to evaluate Cancerelevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients .
21048039
RESULTS : CancerTumors from 312 of 442 patients ( 71 % ) were evaluable by FISH and met the criteria for statistical analysis .
21048039
A moderate increase in EGFR copy number was common , with high-level amplification of the gene occurring in a small fraction of Cancertumors ( ~ 11 % ) .
21048039
CONCLUSION : CancerTumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN .
21067377
BACKGROUND : The genetic alterations responsible for an adverse outcome in most patients with Canceracute myeloid leukemia ( AML ) are unknown .
21067377
DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations , regardless of age , and were independently associated with a AdverseOutcomepoor outcome in Cox proportional-hazards analysis .
21067377
CONCLUSIONS : DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a AdverseOutcomepoor outcome .
21098728
Oncogenic BRAF mutations are found in Cancerseveral tumor types , including melanomas and colorectal cancers .
21098728
Oncogenic BRAF mutations are found in several tumor types , including Cancermelanomas and colorectal cancers .
21098728
Oncogenic BRAF mutations are found in several tumor types , including melanomas and Cancercolorectal cancers .
21098728
CancerTumors with BRAF mutations have increased mitogen activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK ( mitogen activated or extracellular signal regulated protein kinase kinase ) inhibitors .
21098728
To identify potential mechanisms of acquired drug resistance , we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two CancerBRAF V600E mutant colorectal cancer cell lines that are highly sensitive to MEK or BRAF inhibition .
21098728
We observed similar amplification in a subset of cells in a CancerBRAF-mutant colorectal cancer .
21119596
Recently , mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships , contribute to oncogenesis and serve as biomarkers for Cancercancer risk .
21119596
Recently , mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships , contribute to oncogenesis and serve as biomarkers for cancer AdverseOutcomerisk .
21119596
KIT , an established oncogene with a multifaceted role in melanogenesis and Cancermelanoma pathogenesis , has recently been shown to be upregulated in some melanomas , and is also a target of the miRNA miR-221 .
21119596
KIT , an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis , has recently been shown to be upregulated in some Cancermelanomas , and is also a target of the miRNA miR-221 .
21119596
Here , we describe a genetic variant in the 3 ' UTR of the KIT oncogene that correlates with a greater than fourfold increased AdverseOutcomerisk of acral melanoma .
21119596
Here , we describe a genetic variant in the 3 ' UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of Canceracral melanoma .
21119596
This work identifies a novel genetic marker for increased AdverseOutcomeheritable risk of melanoma .
21119596
This work identifies a novel genetic marker for increased heritable risk of Cancermelanoma .
21119661
BACKGROUND : Activating mutations of FGFR3 are frequently identified in Cancersuperficial urothelial carcinoma ( UC ) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC .
21119661
METHODS : The effects of inhibition of receptor activity by three small molecule inhibitors ( PD173074 , TKI-258 and SU5402 ) were investigated in a panel of Cancerbladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status .
21119661
PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of Cancersubcutaneous bladder tumour xenografts .
21135251
CancerMetastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer .
21135251
Metastasis and drug resistance are the major causes of AdverseOutcomemortality in patients with pancreatic cancer .
21135251
Metastasis and drug resistance are the major causes of mortality in patients with Cancerpancreatic cancer .
21135251
Once developed , the progression of Cancerpancreatic cancer metastasis is virtually unstoppable with current therapies .
21135251
Here , we report the remarkable clinical outcome of a patient with advanced , gemcitabine resistant , Cancerpancreatic cancer who was later treated with DNA damaging agents , on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient 's surgically resected tumor .
21135251
Here , we report the remarkable clinical outcome of a patient with advanced , gemcitabine resistant , pancreatic cancer who was later treated with DNA damaging agents , on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient 's surgically Cancerresected tumor .
21135251
Mitomycin C treatment , selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient 's Cancertumor , resulted in long lasting ( 36+ months ) tumor response .
21135251
Mitomycin C treatment , selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient 's tumor , resulted in long lasting ( 36+ months ) Cancertumor response .
21135251
Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient 's Cancercancer ; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair .
21135251
This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in Cancerpancreatic cancer and a new target for personalizing cancer treatment .
21135251
This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing Cancercancer treatment .
21135251
Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy , tailored to the genetic environment of the patient 's Cancertumor , and identification of a new biomarker of drug response in a lethal cancer .
21135251
Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy , tailored to the genetic environment of the patient 's tumor , and identification of a new biomarker of drug response in a Cancerlethal cancer .
21156401
BACKGROUND : Once metastasized , despite a variety of therapeutic options , the prognosis of patients with Cancermalignant melanoma ( MM ) is still poor .
21156401
Therefore , the search for reliable markers to identify patients with AdverseOutcomehigh risk of disease progression is of high clinical importance .
21156401
Therefore , the search for reliable markers to identify patients with high risk of Diseasedisease progression is of high clinical importance .
21156401
We have recently shown that TT genotypes of the single-nucleotide polymorphism ( SNP ) T393C in the gene GNAS1 are significantly associated with better outcome in a variety of Cancercarcinomas .
21156401
- RESULTS : While the allele frequency in the MM group ( fC 0.52 ) did not significantly differ from that of healthy blood donors , the T393C SNP was associated with Cancertumor progression of MM .
21156401
Carriers of the C-allele showed a significantly more Cancersevere tumor progression as estimated from the time period to develop metastasis ( HR 2.2 , 95 % CI 1.1-3 .2 , p = 0.017 ) .
21156401
Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop Cancermetastasis ( HR 2.2 , 95 % CI 1.1-3 .2 , p = 0.017 ) .
21156401
Moreover , multivariable Cox regression analysis including Cancertumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis ( p = 0.012 ) .
21156401
Moreover , multivariable Cox regression analysis including tumor stage and Cancermelanoma subtype proved the T393C polymorphism to be an independent factor for metastasis ( p = 0.012 ) .
21156401
Moreover , multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for Cancermetastasis ( p = 0.012 ) .
21156401
- CONCLUSIONS : In summary , the GNAS1 T393C SNP represents a genetic host factor for predicting Cancertumor progression also in patients with MM ; genotyping of this SNP may contribute to better define patients who could benefit from an early individualized therapy .
21160078
CancerLung cancer remains one of the leading causes of cancer related death in developed countries .
21160078
Lung cancer remains one of the leading causes of Cancercancer related death in developed countries .
21160078
Although Cancerlung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase ( ALK ) inhibition , respectively , squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations .
21160078
Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor ( EGFR ) and Canceranaplastic lymphoma kinase ( ALK ) inhibition , respectively , squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations .
21160078
Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase ( ALK ) inhibition , respectively , Cancersquamous cell lung cancer currently lacks therapeutically exploitable genetic alterations .
21160078
We conducted a systematic search in a set of 232 Cancerlung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses .
21160078
We identified frequent and focal fibroblast growth factor receptor 1 ( FGFR1 ) amplification in Cancersquamous cell lung cancer ( n = 155 ) , but not in other lung cancer subtypes , and , by fluorescence in situ hybridization , confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples ( 22 % of cases ) .
21160078
We identified frequent and focal fibroblast growth factor receptor 1 ( FGFR1 ) amplification in squamous cell lung cancer ( n = 155 ) , but not in Cancerother lung cancer subtypes , and , by fluorescence in situ hybridization , confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples ( 22 % of cases ) .
21160078
We identified frequent and focal fibroblast growth factor receptor 1 ( FGFR1 ) amplification in squamous cell lung cancer ( n = 155 ) , but not in other lung cancer subtypes , and , by fluorescence in situ hybridization , confirmed the presence of FGFR1 amplifications in an independent cohort of Cancersquamous cell lung cancer samples ( 22 % of cases ) .
21160078
Using cell based screening with the FGFR inhibitor PD173074 in a large ( n = 83 ) panel of Cancerlung cancer cell lines , we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1 .
21160078
Using cell based screening with the FGFR inhibitor PD173074 in a large ( n = 83 ) panel of lung cancer cell lines , we demonstrated that this compound inhibited growth and induced apoptosis specifically in those Cancerlung cancer cells carrying amplified FGFR1 .
21160078
Finally , we showed that inhibition of FGFR1 with a small molecule led to Cancersignificant tumor shrinkage in vivo .
21160078
Thus , focal FGFR1 amplification is common in Cancersquamous cell lung cancer and associated with tumor growth and survival , suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients .
21160078
Thus , focal FGFR1 amplification is common in squamous cell lung cancer and associated with Cancertumor growth and survival , suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients .
21163703
The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor ( EGFR ) monoclonal antibodies brought a major change in the treatment of Cancermetastatic colorectal cancer .
21163703
This seminal finding also highlighted our sparse knowledge about key signalling pathways in Cancercolorectal tumours .
21163703
However , our understanding of the precise role these potential drug targets have in Cancercolorectal tumours , and the oncogenic dependence that tumours might have on these components , has not progressed at the same rate .
21163703
However , our understanding of the precise role these potential drug targets have in colorectal tumours , and the oncogenic dependence that Cancertumours might have on these components , has not progressed at the same rate .
21166657
BACKGROUND : There have been conflicting data regarding the prevalence and clinicopathological characteristics of BRAF and NRAS mutations in Cancerprimary cutaneous melanoma .
21166657
OBJECTIVES : To solve this controversy , this study used a meta-analysis to evaluate the frequencies of BRAF and NRAS mutations , and the relationship between these mutations and clinicopathological parameters of Cancercutaneous melanoma .
21166657
RESULTS : BRAF and NRAS mutations were reported in 41 % and 18 % of Cancercutaneous melanomas , respectively .
21166657
The mutations were associated with histological subtype and Cancertumour site , but not with age and sex .
21166657
The BRAF mutation was frequently detected in patients with Cancersuperficial spreading melanoma ( OR = 2.021 ; P < 0.001 ) and in melanomas arising in nonchronic sun damaged skin ( OR = 2.043 ; P = 0.001 ) .
21166657
The BRAF mutation was frequently detected in patients with superficial spreading melanoma ( OR = 2.021 ; P < 0.001 ) and in Cancermelanomas arising in nonchronic sun damaged skin ( OR = 2.043 ; P = 0.001 ) .
21166657
In contrast , the NRAS mutation was frequently evident in patients with Cancernodular melanoma ( OR = 1.894 ; P < 0.001 ) and in melanomas arising in chronic sun damaged skin ( OR = 1.887 ; P = 0.018 ) .
21166657
In contrast , the NRAS mutation was frequently evident in patients with nodular melanoma ( OR = 1.894 ; P < 0.001 ) and in Cancermelanomas arising in chronic sun damaged skin ( OR = 1.887 ; P = 0.018 ) .
21166657
CONCLUSIONS : This pooled analysis shows that the incidences of BRAF and NRAS mutations in Cancercutaneous melanomas differ according to histological type and tumour location based on the degree of sun exposure .
21166657
CONCLUSIONS : This pooled analysis shows that the incidences of BRAF and NRAS mutations in cutaneous melanomas differ according to histological type and Cancertumour location based on the degree of sun exposure .
21172893
PURPOSE : The antibody-drug conjugate trastuzumab-DM1 ( T-DM1 ) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent , DM1 , to human epidermal growth factor receptor 2 ( CancerHER2 )-overexpressing cancer cells .
21172893
Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum tolerated dose of 3.6 mg/kg every 3 weeks , with evidence of efficacy , in patients with CancerHER2 positive metastatic breast cancer ( MBC ) who were previously treated with trastuzumab , we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population .
21172893
PATIENTS AND METHODS : This report describes a single-arm phase II study ( TDM4258g ) that assessed efficacy and safety of intravenous T-DM1 ( 3.6 mg/kg every 3 weeks ) in patients with HER2 positive MBC who had Cancertumor progression after prior treatment with HER2 directed therapy and who had received prior chemotherapy .
21172893
The response rates were higher among patients with confirmed CancerHER2 positive tumors ( immunohistochemistry 3+ or fluorescent in situ hybridization positive ) by retrospective central testing ( n = 74 ) .
21172893
Higher response rates were also observed in patients whose Cancertumors expressed > = median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression , compared with patients who had less than median HER2 levels .
21172893
Most adverse events ( AEs ) were grade 1 or 2 ; the most frequent grade > = 3 AEs were Diseasehypokalemia ( 8.9 % ) , thrombocytopenia ( 8.0 % ) , and fatigue ( 4.5 % ) .
21172893
Most adverse events ( AEs ) were grade 1 or 2 ; the most frequent grade > = 3 AEs were hypokalemia ( 8.9 % ) , Diseasethrombocytopenia ( 8.0 % ) , and fatigue ( 4.5 % ) .
21177507
CONTEXT : Germline loss-of-function phosphatase and tensin homolog gene ( PTEN ) mutations cause 80 % of DiseaseCowden syndrome , a rare autosomal dominant disorder ( 1 in 200,000 live births ) , characterized by high risks of breast , thyroid , and other cancers .
21177507
CONTEXT : Germline loss-of-function phosphatase and tensin homolog gene ( PTEN ) mutations cause 80 % of Cowden syndrome , a Diseaserare autosomal dominant disorder ( 1 in 200,000 live births ) , characterized by high risks of breast , thyroid , and other cancers .
21177507
CONTEXT : Germline loss-of-function phosphatase and tensin homolog gene ( PTEN ) mutations cause 80 % of Cowden syndrome , a rare autosomal dominant disorder ( 1 in 200,000 live births ) , characterized by AdverseOutcomehigh risks of breast , thyroid , and other cancers .
21177507
CONTEXT : Germline loss-of-function phosphatase and tensin homolog gene ( PTEN ) mutations cause 80 % of Cowden syndrome , a rare autosomal dominant disorder ( 1 in 200,000 live births ) , characterized by high risks of breast , thyroid , and Cancerother cancers .
21177507
A large heterogeneous group of individuals with Cowden like Diseasesyndrome , who have various combinations of Cowden syndrome features but who do not meet Cowden syndrome diagnostic criteria , have PTEN mutations less than 10 % of the time , making molecular diagnosis , prediction , genetic counseling , and risk management challenging .
21177507
A large heterogeneous group of individuals with Cowden like syndrome , who have various combinations of DiseaseCowden syndrome features but who do not meet Cowden syndrome diagnostic criteria , have PTEN mutations less than 10 % of the time , making molecular diagnosis , prediction , genetic counseling , and risk management challenging .
21177507
A large heterogeneous group of individuals with Cowden like syndrome , who have various combinations of Cowden syndrome features but who do not meet DiseaseCowden syndrome diagnostic criteria , have PTEN mutations less than 10 % of the time , making molecular diagnosis , prediction , genetic counseling , and risk management challenging .
21177507
A large heterogeneous group of individuals with Cowden like syndrome , who have various combinations of Cowden syndrome features but who do not meet Cowden syndrome diagnostic criteria , have PTEN mutations less than 10 % of the time , making molecular diagnosis , prediction , genetic counseling , and AdverseOutcomerisk management challenging .
21177507
Other mechanisms of loss of function such as hypermethylation , which should result in underexpression of PTEN or of KILLIN , a novel tumor suppressor transcribed in the opposite direction , may account for the remainder of DiseaseCowden syndrome and Cowden like syndrome .
21177507
Other mechanisms of loss of function such as hypermethylation , which should result in underexpression of PTEN or of KILLIN , a novel tumor suppressor transcribed in the opposite direction , may account for the remainder of Cowden syndrome and Cowden like Diseasesyndrome .
21177507
OBJECTIVE : To determine whether germline methylation is found in DiseaseCowden syndrome or Cowden like syndrome in individuals lacking germline PTEN mutations .
21177507
OBJECTIVE : To determine whether germline methylation is found in Cowden syndrome or Cowden like Diseasesyndrome in individuals lacking germline PTEN mutations .
21177507
DESIGN , SETTING , AND PARTICIPANTS : Nucleic acids from prospective nested series of 123 patients with DiseaseCowden syndrome or Cowden like syndrome and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN at the Cleveland Clinic , August 2008-June 2010 .
21177507
DESIGN , SETTING , AND PARTICIPANTS : Nucleic acids from prospective nested series of 123 patients with Cowden syndrome or Cowden like Diseasesyndrome and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN at the Cleveland Clinic , August 2008-June 2010 .
21177507
Prevalence of Cancercomponent cancers between groups was compared using the Fisher exact test .
21177507
MAIN OUTCOME MEASURES : Frequency of germline methylation in DiseasePTEN mutation negative Cowden syndrome and Cowden syndrome like individuals .
21177507
MAIN OUTCOME MEASURES : Frequency of germline methylation in PTEN mutation negative Cowden syndrome and DiseaseCowden syndrome like individuals .
21177507
Prevalence of Cancercomponent cancers in methylation positive and PTEN mutation positive individuals .
21177507
RESULTS : Of 123 patients with DiseaseCowden syndrome or Cowden like syndrome , 45 ( 37 % ; 95 % confidence interval [ CI ] , 29 %-45% ) showed hypermethylation upstream of PTEN but no transcriptional repression .
21177507
RESULTS : Of 123 patients with Cowden syndrome or Cowden like Diseasesyndrome , 45 ( 37 % ; 95 % confidence interval [ CI ] , 29 %-45% ) showed hypermethylation upstream of PTEN but no transcriptional repression .
21177507
Individuals with KILLIN -promoter methylation had a 3-fold increased prevalence of Cancerbreast cancer ( 35/42 vs 24/64 ; P < .0001 ) and a greater than 2-fold increase of kidney cancer ( 4/45 vs 6/155 ; P = .004 ) over individuals with germline PTEN mutations .
21177507
Individuals with KILLIN -promoter methylation had a 3-fold increased prevalence of breast cancer ( 35/42 vs 24/64 ; P < .0001 ) and a greater than 2-fold increase of Cancerkidney cancer ( 4/45 vs 6/155 ; P = .004 ) over individuals with germline PTEN mutations .
21177507
CONCLUSIONS : Germline KILLIN methylation is common among patients with DiseaseCowden syndrome or Cowden like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation positive individuals .
21177507
CONCLUSIONS : Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden like Diseasesyndrome and is associated with increased risks of breast and renal cancer over PTEN mutation positive individuals .
21177507
CONCLUSIONS : Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden like syndrome and is associated with increased AdverseOutcomerisks of breast and renal cancer over PTEN mutation positive individuals .
21177507
CONCLUSIONS : Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden like syndrome and is associated with increased risks of breast and Cancerrenal cancer over PTEN mutation positive individuals .
21258415
Heat shock protein 90 ( Hsp90 ) is an emerging target for Cancercancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins .
21258415
We show here that the echinoderm microtubule associated protein like 4 ( CancerEML4 )-anaplastic lymphoma kinase ( ALK ) fusion protein , presumed to be the oncogenic driver in about 5 % of patients with non small cell lung cancer ( NSCLC ) , is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504 .
21258415
We show here that the echinoderm microtubule associated protein like 4 ( EML4 )-anaplastic lymphoma kinase ( ALK ) fusion protein , presumed to be the oncogenic driver in about 5 % of patients with Cancernon small cell lung cancer ( NSCLC ) , is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504 .
21258415
In a xenograft model of a human NSCLC cell line containing the ALK rearrangement , we observe Cancertumor regression at clinically relevant doses of IPI-504 .
21278246
PURPOSE : PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block Cancerretinoblastoma ( Rb ) phosphorylation in the low nanomolar range .
21278246
Here we investigate the role of CDK4/6 inhibition in Cancerhuman ovarian cancer .
21278246
EXPERIMENTAL DESIGN : We examined the effects of PD-0332991 on proliferation , cell-cycle , apoptosis , and Rb phosphorylation using a panel of 40 Cancerestablished human ovarian cancer cell lines .
21278246
Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of Cancerovarian cancer patients .
21278246
RESULTS : Concentration dependent antiproliferative effects of PD-0332991 were seen in all Cancerovarian cancer cell lines , but varied significantly between individual lines .
21278246
Rb-proficiency with low p16 expression was seen in 97/262 ( 37 % ) of Cancerovarian cancer patients and was independently associated with poor progression-free survival ( adjusted relative risk 1.49 , 95 % CI 1.00-2 .24 , P = 0.052 ) .
21278246
Rb-proficiency with low p16 expression was seen in 97/262 ( 37 % ) of ovarian cancer patients and was independently associated with poor progression-free survival ( adjusted AdverseOutcomerelative risk 1.49 , 95 % CI 1.00-2 .24 , P = 0.052 ) .
21278246
CONCLUSIONS : PD-0332991 shows promising biologic activity in Cancerovarian cancer cell lines .
21278246
Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in Cancerovarian cancer .
21309036
Recently , we identified 3 ' end deletions in the EPCAM gene as a novel cause of DiseaseLynch syndrome .
21309036
Within The Netherlands and Germany , EPCAM deletions appeared to represent at least 2.8 % and 1.1 % of the Diseaseconfirmed Lynch syndrome families , respectively .
21309036
We conclude that 3 ' end EPCAM deletions are a recurrent cause of DiseaseLynch syndrome , which should be implemented in routine Lynch syndrome diagnostics .
21309036
We conclude that 3 ' end EPCAM deletions are a recurrent cause of Lynch syndrome , which should be implemented in Diseaseroutine Lynch syndrome diagnostics .
21309039
The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict , and the identification of such variants in individuals at AdverseOutcomerisk of a genetic disease can complicate genetic counselling .
21309039
The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict , and the identification of such variants in individuals at risk of a Diseasegenetic disease can complicate genetic counselling .
21331613
Expression of the O ( 6 )-methylguanine-DNA methyltransferase ( MGMT ) gene has been shown to correlate with clinical outcomes in patients with Cancerglioblastoma multiforme treated with alkylating agents .
21331613
We evaluated MGMT protein expression in 53 Cancerprimary glioblastomas by the immunohistochemistry ( IHC ) and analyzed the correlation between results of immunostaining and patient outcomes .
21331613
There were 28 MGMT-immunopositive and 25 Cancernegative glioblastomas .
21331613
Patients with CancerMGMT-immunonegative glioblastomas showed significantly longer progression-free survival ( PFS ) ( P = 0.0032 ) , but no statistically significant benefits on overall survival ( OS ) ( P = 0.0825 ) were shown .
21331613
In 41 Cancerglioblastomas treated with temozolomide ( TMZ ) therapy ( MGMT-immunopositive : n = 22 , negative : n = 19 ) , both PFS and OS were significantly better in MGMT-immunonegative glioblastomas .
21331613
In 41 glioblastomas treated with temozolomide ( TMZ ) therapy ( MGMT-immunopositive : n = 22 , negative : n = 19 ) , both PFS and OS were significantly better in CancerMGMT-immunonegative glioblastomas .
21331613
We conclude that MGMT expression on immunohistochemistry ( IHC ) correlates with outcomes in patients with Cancerprimary glioblastoma receiving TMZ and suggest the use of MGMT-IHC as a surrogate marker for predicting tumor chemosensitivity .
21331613
We conclude that MGMT expression on immunohistochemistry ( IHC ) correlates with outcomes in patients with primary glioblastoma receiving TMZ and suggest the use of MGMT-IHC as a surrogate marker for predicting Cancertumor chemosensitivity .
21343549
PURPOSE : To determine the frequency of TET2 mutations , their associations with clinical and molecular characteristics and outcome , and the associated gene- and microRNA expression signatures in patients with primary cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) .
21343560
PURPOSE : To evaluate frequency , biologic features , and clinical relevance of RUNX1 mutations in Canceracute myeloid leukemia ( AML ) .
21343560
RUNX1 mutations clustered in the intermediate-risk cytogenetic group ( 46 of 640 , 7.2 % ; cytogenetically normal , 34 of 538 , 6.3 % ) , whereas they were less frequent in adverse-risk cytogenetics ( five of 109 , 4.6 % ) and absent in core-binding-factor AML ( 0 of 77 ) and Canceracute promyelocytic leukemia ( 0 of 61 ) .
21343560
RUNX1 mutations predicted for resistance to chemotherapy ( rates of Diseaserefractory disease 30 % and 19 % , P = .047 , for RUNX1 mutated and wild-type patients , respectively ) , as well as inferior event-free survival ( EFS ; P < .0001 ) , relapse-free survival ( RFS , P = .022 ) , and overall survival ( P = .051 ) .
21358673
The phosphatidylinositol 3-kinase ( PI3K ) pathway is commonly activated in Cancerbreast cancers due to frequent mutations in PIK3CA , loss of expression of PTEN or over-expression of receptor tyrosine kinases .
21358673
PI3K pathway activation leads to stimulation of the key growth and proliferation regulatory kinase mammalian target of rapamycin ( mTOR ) , which can be inhibited by rapamycin analogues and by kinase inhibitors ; the effectiveness of these drugs in Cancerbreast cancer treatment is currently being tested in clinical trials .
21358673
To identify the molecular determinants of response to inhibitors that target mTOR via different mechanisms in Cancerbreast cancer cells , we investigated the effects of pharmacological inhibition of mTOR using the allosteric mTORC1 inhibitor everolimus and the active-site mTORC1 and mTORC2 kinase inhibitor PP242 on a panel of 31 breast cancer cell lines .
21358673
To identify the molecular determinants of response to inhibitors that target mTOR via different mechanisms in breast cancer cells , we investigated the effects of pharmacological inhibition of mTOR using the allosteric mTORC1 inhibitor everolimus and the active-site mTORC1 and mTORC2 kinase inhibitor PP242 on a panel of 31 Cancerbreast cancer cell lines .
21358673
We demonstrate here that Cancerbreast cancer cells harbouring PIK3CA mutations are selectively sensitive to mTOR allosteric and kinase inhibitors .
21358673
Our findings provide a rationale to guide selection of Cancerbreast cancer patients who may benefit from mTOR inhibitor therapy and highlight the importance of accurately assessing the expression of PTEN protein and not just its mutational status .
21365007
BACKGROUND : We analyzed prospectively whether MGMT ( O ( 6 )-methylguanine-DNA methyltransferase ) mRNA expression gains prognostic and predictive impact independent of MGMT promoter methylation in Cancermalignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone .
21365007
METHODOLOGY and PRINCIPAL FINDINGS : ADULT PATIENTS WITH A CancerHISTOLOGICALLY PROVEN MALIGNANT ASTROCYTOMA ( GLIOBLASTOMA : N = 53 , anaplastic astrocytoma : N = 10 ) were included .
21365007
METHODOLOGY and PRINCIPAL FINDINGS : ADULT PATIENTS WITH A HISTOLOGICALLY PROVEN MALIGNANT ASTROCYTOMA ( GLIOBLASTOMA : N = 53 , Canceranaplastic astrocytoma : N = 10 ) were included .
21365007
Correlation between MGMT mRNA expression and MGMT methylation status was validated using data from the CancerCancer Genome Atlas ( TCGA ) database ( N = 229 glioblastomas ) .
21365007
Correlation between MGMT mRNA expression and MGMT methylation status was validated using data from the Cancer Genome Atlas ( TCGA ) database ( N = 229 Cancerglioblastomas ) .
21365007
Low MGMT mRNA expression was strongly predictive for prolonged time to progression , treatment response , and length of survival in univariate and multivariate models ( p < 0.0001 ) ; the degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status ( p < 0.0001 ) ; however , discordant findings were seen in 12 Cancerglioblastoma patients : Patients with methylated tumors with high MGMT mRNA expression ( N = 6 ) did significantly worse than those with low transcriptional activity ( p < 0.01 ) .
21365007
Low MGMT mRNA expression was strongly predictive for prolonged time to progression , treatment response , and length of survival in univariate and multivariate models ( p < 0.0001 ) ; the degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status ( p < 0.0001 ) ; however , discordant findings were seen in 12 glioblastoma patients : Patients with methylated Cancertumors with high MGMT mRNA expression ( N = 6 ) did significantly worse than those with low transcriptional activity ( p < 0.01 ) .
21365007
Conversely , Cancerunmethylated tumors with low MGMT mRNA expression ( N = 6 ) did better than their counterparts .
21365007
Expression of DNMT1 and DNMT3b was strongly upregulated in Cancertumor tissue , but not correlated with MGMT promoter methylation and MGMT mRNA expression .
21365007
CONCLUSIONS and SIGNIFICANCE : MGMT mRNA expression plays a direct role for mediating Cancertumor sensitivity to alkylating agents .
21367480
Thymidylate synthase ( TS ) and dihydrofolate reductase ( DHFR ) are target enzymes of inhibition by pemetrexed , an antifolate for treatment of Canceradvanced non-small-cell lung cancer ( NSCLC ) .
21367480
The TS and DHFR expressions in Cancertumor tissues were examined by immunohistochemistry and evaluated by a semiquantitative histologic score ( H-score ) .
21367480
The H-score was derived from the degrees of intensity of Cancertumor cells multiplied by the percentage of positive neoplastic cells .
21367480
Among 268 NSCLC patients treated with pemetrexed , 49 had Cancertumor specimens available for TS and DHFR evaluation .
21367480
In patients with Canceradenocarcinoma , the low TS patient group also had a longer median PFS and a longer median overall survival ( OS ) as compared with patients with high TS expression ( PFS , 4.8 vs. 3.8 months , p = 0.03 ; OS , 21.4 vs. 10.0 months , p = 0.03 ) .
21383288
A detailed understanding of the mechanisms by which Cancertumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy .
21383288
RAF inhibition in CancerBRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs ; although response rates are high , resistance invariably develops .
21383288
Here , we articulate overarching principles of resistance to kinase inhibitors , as well as a translational approach to characterize resistance in the clinical setting through Cancertumor mutation profiling .
21383288
As a proof of principle , we performed targeted , massively parallel sequencing of 138 Cancercancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response .
21383288
As a proof of principle , we performed targeted , massively parallel sequencing of 138 cancer genes in a Cancertumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response .
21383288
As a proof of principle , we performed targeted , massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with Cancermelanoma who developed resistance to PLX4032 after an initial dramatic response .
21383288
The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the Cancercorresponding pretreatment tumor .
21383288
These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate Cancerpersonalized cancer medicine .
21415852
Alterations in DNA methylation have been implicated in the pathogenesis of Diseasemyelodysplastic syndromes ( MDS ) , although the underlying mechanism remains largely unknown .
21415852
DNMT3A mutations have recently been reported in patients with de novo Canceracute myeloid leukemia ( AML ) , providing a rationale for examining the status of DNMT3A in MDS samples .
21422407
PURPOSE : The Tamoxifen and Exemestane Adjuvant Multinational ( TEAM ) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor ( PgR ) expression for outcome of estrogen receptor positive ( ER positive ) Cancerearly breast cancer treated with exemestane versus tamoxifen .
21422407
CONCLUSION : Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression ; conversely , patients with CancerER rich tumors may derive additional benefit from exemestane .
21422407
Quantitative analysis of ER and PgR expression provides highly significant information on AdverseOutcomerisk of early relapse ( within 1 to 3 years ) during treatment .
21422803
BACKGROUND : CancerMedullary thyroid cancer ( MTC ) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor ( VEGF ) and VEGF receptor 2 ( VEGFR2 ) .
21422803
AIM : The aim of this study was to investigate the effects of motesanib on wildtype and mutant Ret activity in vitro and on Cancertumor xenograft growth in a mouse model of MTC .
21422803
In vivo , motesanib significantly inhibited the growth of CancerTT tumor cell xenografts ( expressing Ret C634W ) and significantly reduced tumor blood vessel area and tumor cell proliferation , compared with control .
21422803
In vivo , motesanib significantly inhibited the growth of TT tumor cell xenografts ( expressing Ret C634W ) and significantly reduced Cancertumor blood vessel area and tumor cell proliferation , compared with control .
21422803
In vivo , motesanib significantly inhibited the growth of TT tumor cell xenografts ( expressing Ret C634W ) and significantly reduced tumor blood vessel area and Cancertumor cell proliferation , compared with control .
21422803
CONCLUSIONS : The results of this study demonstrate that motesanib inhibited Cancerthyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on tumor cells .
21422803
CONCLUSIONS : The results of this study demonstrate that motesanib inhibited thyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on Cancertumor cells .
21430269
CancerLung cancers harboring mutations in the epidermal growth factor receptor ( EGFR ) respond to EGFR tyrosine kinase inhibitors , but drug resistance invariably emerges .
21430269
To elucidate mechanisms of acquired drug resistance , we performed systematic genetic and histological analyses of Cancertumor biopsies from 37 patients with drug resistant non small cell lung cancers ( NSCLCs ) carrying EGFR mutations .
21430269
To elucidate mechanisms of acquired drug resistance , we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with Cancerdrug resistant non small cell lung cancers ( NSCLCs ) carrying EGFR mutations .
21430269
All Cancerdrug resistant tumors retained their original activating EGFR mutations , and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification .
21430269
Some Cancerresistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene , whereas others underwent a pronounced epithelial-to-mesenchymal transition .
21430269
Surprisingly , five Cancerresistant tumors ( 14 % ) transformed from NSCLC into small cell lung cancer ( SCLC ) and were sensitive to standard SCLC treatments .
21430269
Surprisingly , five resistant tumors ( 14 % ) transformed from NSCLC into Cancersmall cell lung cancer ( SCLC ) and were sensitive to standard SCLC treatments .
21430269
In three patients , serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment , and Cancersuch cancers were sensitive to a second round of treatment with EGFR inhibitors .
21430269
Collectively , these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing Cancercancers throughout the course of the disease .
21430269
Collectively , these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the Diseasedisease .
21458988
We examined the prognostic and predictive impact of DNA methyltransferase ( DNMT ) 1 and 3b expression in Cancergastric carcinomas ( GC ) treated by neoadjuvant chemotherapy .
21458988
RESULTS : High DNMT1 and DNMT3b expression was found in 105/127 ( 83 % ) and 79/127 ( 62 % ) Cancercarcinomas , respectively .
21461300
BACKGROUND : All-trans retinoic acid ( ATRA )/anthracycline chemotherapy is beneficial in newly diagnosed Canceracute promyelocytic leukemia ( APL ) ; however , it is important to identify patients with high-risk disease to increase the cure rate .
21461300
BACKGROUND : All-trans retinoic acid ( ATRA )/anthracycline chemotherapy is beneficial in newly diagnosed acute promyelocytic leukemia ( APL ) ; however , it is important to identify patients with Diseasehigh-risk disease to increase the cure rate .
21461300
Multivariate analysis of the LFS showed that the FLT3 and ITD mutation was independently associated with a shorter overall LFS , after adjusting for pretreatment AdverseOutcomerisk stratification .
21467160
PURPOSE : TP53 is a key gene in cellular homeostasis and is frequently mutated in head and Cancerneck squamous cell carcinoma ( HNSCC ) .
21467160
EXPERIMENTAL DESIGN : TP53 mutation status was investigated in 141 consecutive HNSCCs treated by surgery with radiotherapy when indicated and with a Cancerknown human papilloma virus status .
21467160
RESULTS : A TP53 mutation was found in 88 ( 62.4 % ) of the Cancercarcinomas and was not significantly associated with overall survival ( HR = 1.65 , P = 0.11 ) .
21467160
CONCLUSION : In HNSCCs , a truncating TP53 mutation is associated with a AdverseOutcomepoor prognosis .
21483000
PURPOSE : TP53 mutations have been described in Cancerchronic lymphocytic leukemia ( CLL ) and have been associated with poor prognosis in retrospective studies .
21483000
PURPOSE : TP53 mutations have been described in chronic lymphocytic leukemia ( CLL ) and have been associated with AdverseOutcomepoor prognosis in retrospective studies .
21483000
PATIENTS AND METHODS : We analyzed 529 CLL samples from the LRF CLL4 ( CancerLeukaemia Research Foundation Chronic Lymphocytic Leukemia 4 ) trial ( chlorambucil v fludarabine with or without cyclophosphamide ) at the time of random assignment for mutations in the TP53 gene .
21483000
Analysis of TP53 mutations should be performed in patients with CLL who have Diseaseprogressive disease before starting first-line treatment , and those with mutations should be selected for novel experimental therapies .
21494621
CancerALK positive diffuse large B-cell lymphomas ( DLBCL ) are a distinct lymphoma subtype associated with a poor outcome .
21494621
ALK positive diffuse large B-cell lymphomas ( DLBCL ) are a Cancerdistinct lymphoma subtype associated with a poor outcome .
21494621
ALK positive diffuse large B-cell lymphomas ( DLBCL ) are a distinct lymphoma subtype associated with a AdverseOutcomepoor outcome .
21494621
LM1 formed Cancertumors in NOD-SCID mice .
21494621
Inhibition of ALK activity resulted in Cancersustained tumor regression in the xenotransplant tumor model .
21494621
Inhibition of ALK activity resulted in sustained tumor regression in the Cancerxenotransplant tumor model .
21494621
These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise Cancerrefractory tumors .
21505136
DESIGN , SETTING , AND PATIENT : We were referred a difficult diagnostic case of Canceracute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase fluorescence in situ hybridization ( FISH ) .
21505136
Novel FISH probes identified 2 additional cases of t ( 15 ; 17 Cancer)-negative acute promyelocytic leukemia that had cytogenetically invisible insertions .
21537333
In conclusion , for AdverseOutcomerisk estimation in NPM1 mutated AML not only the FLT3-ITD status , but also the FLT3-ITD load has to be taken into account .
21558396
PURPOSE : The phosphatidylinositol 3-kinase ( PI3K ) pathway plays a central role in cell proliferation and survival in Cancerhuman cancer .
21558396
PIK3CA mutations , which are found in Cancermany cancer patients , activate the PI3K pathway , resulting in cancer development and progression .
21558396
PIK3CA mutations , which are found in many cancer patients , activate the PI3K pathway , resulting in Cancercancer development and progression .
21558396
A large panel of human breast , ovarian , prostate , and Cancerendometrial cancer cell lines , as well as xenograft models , were used to evaluate the antitumor activity of CH5132799 , followed by analysis for genetic alterations .
21558396
CancerTumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models .
21558396
In combination with trastuzumab , Cancertumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation .
21558396
In combination with trastuzumab , tumors disappeared in the Cancertrastuzumab-insensitive breast cancer model with the PIK3CA mutation .
21558396
Moreover , CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against Cancertumors regrown after long-term mTORC1 inhibitor treatment .
21558396
CONCLUSIONS : CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against Cancertumors harboring the PIK3CA mutations .
21575866
CancerAnaplastic lymphoma kinase ( ALK ) is a tyrosine kinase that is constitutively activated in certain cancers , following gene alterations such as chromosomal translocation , amplification , or point mutation .
21575866
Anaplastic lymphoma kinase ( ALK ) is a tyrosine kinase that is constitutively activated in Cancercertain cancers , following gene alterations such as chromosomal translocation , amplification , or point mutation .
21575866
Here , we identified CH5424802 , a potent , selective , and orally available ALK inhibitor with a unique chemical scaffold , showing preferential antitumor activity against Cancercancers with gene alterations of ALK , such as nonsmall cell lung cancer ( NSCLC ) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma ( ALCL ) cells expressing NPM-ALK fusion in vitro and in vivo .
21575866
Here , we identified CH5424802 , a potent , selective , and orally available ALK inhibitor with a unique chemical scaffold , showing preferential antitumor activity against cancers with gene alterations of ALK , such as Cancernonsmall cell lung cancer ( NSCLC ) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma ( ALCL ) cells expressing NPM-ALK fusion in vitro and in vivo .
21575866
Here , we identified CH5424802 , a potent , selective , and orally available ALK inhibitor with a unique chemical scaffold , showing preferential antitumor activity against cancers with gene alterations of ALK , such as nonsmall cell lung cancer ( NSCLC ) cells expressing EML4-ALK fusion and Canceranaplastic large-cell lymphoma ( ALCL ) cells expressing NPM-ALK fusion in vitro and in vivo .
21575866
Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK driven Cancertumors .
21576762
Class III beta-tubulin ( beta3 ) is associated with Cancertumor aggressiveness , resistance to therapy , and patient relapse .
21576762
The results provide a potential explanation for the aggressiveness of beta3 expressing Cancertumors .
21584898
The classification of Cancerepithelioid vascular tumors remains challenging , as there is considerable morphological overlap between tumor subtypes , across the spectrum from benign to malignant categories .
21584898
The classification of epithelioid vascular tumors remains challenging , as there is considerable morphological overlap between Cancertumor subtypes , across the spectrum from benign to malignant categories .
21584898
A t ( 1 ; 3 ) ( p36 .3 ; q25 ) translocation was reported in two cases of Cancerepithelioid hemangioendothelioma ( EHE ) , however , no follow-up studies have been performed to identify the gene fusion or to assess its prevalence in a larger cohort of patients .
21584898
For comparison , we analyzed 13 Cancerepithelioid hemangiomas , five epithelioid angiosarcomas , and four epithelioid sarcoma like EHE .
21584898
For comparison , we analyzed 13 epithelioid hemangiomas , five Cancerepithelioid angiosarcomas , and four epithelioid sarcoma like EHE .
21584898
For comparison , we analyzed 13 epithelioid hemangiomas , five epithelioid angiosarcomas , and four Cancerepithelioid sarcoma like EHE .
21584898
None of the other benign or Cancermalignant epithelioid vascular tumors examined demonstrated these abnormalities .
21594665
Trastuzumab ( T ) is effective in Cancermetastatic breast cancer ( MBC ) with HER2 overexpression and/or amplification , but resistance to T develops in a significant number of HER2 positive patients .
21594665
Formalin fixed Cancerparaffin embedded tumor tissue samples were collected from 256 patients with T treated MBC .
21594665
Higher AdverseOutcomerisk of progression was associated with HER2 positive status and the presence of PIK3CA mutations ( P = 0.014 ) .
21594665
In this Cancertrastuzumab treated breast cancer population , PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival .
21594703
PURPOSE : This study was designed to examine the aggressive features of CancerBRAF positive papillary thyroid cancer ( PTC ) and association with age .
21594703
RESULTS : Younger and elderly PTC patients had similar incidences of CancerBRAF positive tumors ( 41 % vs. 38 % ; p = 0.67 ) .
21594703
The elderly cohort was more likely to have Cancersmaller tumors ( mean 1.6 vs. 2.1 cm ; p = 0.001 ) , present with advanced TNM stage ( 36 % vs. 19 % ; p = 0.008 ) , and have persistent and recurrent disease ( 10 % vs. 1 % ; p = 0.006 ) .
21594703
The elderly cohort was more likely to have smaller tumors ( mean 1.6 vs. 2.1 cm ; p = 0.001 ) , present with advanced TNM stage ( 36 % vs. 19 % ; p = 0.008 ) , and have persistent and Diseaserecurrent disease ( 10 % vs. 1 % ; p = 0.006 ) .
21594703
BRAF positive status was associated with PTC that were tall cell variant ( p < 0.001 ) , had extrathyroidal extension ( p < 0.001 ) , lymph node involvement ( p = 0.008 ) , advanced ( III/IV ) TNM stage ( p < 0.001 ) , and Diseasedisease recurrence ( p < 0.001 ) .
21596855
We have investigated the prognostic significance of isocitrate dehydrogenase 2 ( IDH2 ) mutations in 1473 Canceryounger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials .
21613260
Arsenic trioxide ( As2O3 ) is a highly effective treatment for patients with refractory and relapsed Canceracute promyelocytic leukemia ( APL ) , but resistance to As2O3 has recently been seen .
21613260
CancerLeukemia cells from these 2 patients harbored missense mutations in promyelocytic leukemia gene-retinoic acid receptor-alpha gene ( PML-RARA ) transcripts , resulting in amino acid substitutions of A216V and L218P in the PML B2 domain .
21613260
Leukemia cells from these 2 patients harbored missense mutations in Cancerpromyelocytic leukemia gene-retinoic acid receptor-alpha gene ( PML-RARA ) transcripts , resulting in amino acid substitutions of A216V and L218P in the PML B2 domain .
21623265
Currently , clinical development of crizotinib is focused primarily on ALK rearranged Cancernon small cell lung cancer ( NSCLC ) .
21639808
BACKGROUND : Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib ( PLX4032 ) have shown response rates of more than 50 % in patients with Cancermetastatic melanoma with the BRAF V600E mutation .
21639808
METHODS : We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated , Cancermetastatic melanoma with the BRAF V600E mutation .
21639808
In the interim analysis for overall survival and final analysis for progression-free survival , vemurafenib was associated with a relative reduction of 63 % in the AdverseOutcomerisk of death and of 74 % in the risk of either death or disease progression , as compared with dacarbazine ( P < 0.001 for both comparisons ) .
21639808
In the interim analysis for overall survival and final analysis for progression-free survival , vemurafenib was associated with a relative reduction of 63 % in the risk of death and of 74 % in the AdverseOutcomerisk of either death or disease progression , as compared with dacarbazine ( P < 0.001 for both comparisons ) .
21639808
In the interim analysis for overall survival and final analysis for progression-free survival , vemurafenib was associated with a relative reduction of 63 % in the risk of death and of 74 % in the risk of either death or Diseasedisease progression , as compared with dacarbazine ( P < 0.001 for both comparisons ) .
21639808
Common adverse events associated with vemurafenib were arthralgia , rash , fatigue , alopecia , Cancerkeratoacanthoma or squamous-cell carcinoma , photosensitivity , nausea , and diarrhea ; 38 % of patients required dose modification because of toxic effects .
21639808
Common adverse events associated with vemurafenib were arthralgia , rash , fatigue , alopecia , keratoacanthoma or Cancersquamous-cell carcinoma , photosensitivity , nausea , and diarrhea ; 38 % of patients required dose modification because of toxic effects .
21639808
CONCLUSIONS : Vemurafenib produced improved rates of overall and progression-free survival in patients with previously Canceruntreated melanoma with the BRAF V600E mutation .
21642685
CONTEXT : Some Cancermelanomas arising from acral , mucosal , and chronically sun damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT .
21642685
We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of Diseasedisease .
21642685
OBJECTIVE : To assess clinical effects of imatinib mesylate in patients with Cancermelanoma harboring KIT alterations .
21642685
DESIGN , SETTING , AND PATIENTS : A single-group , open-label , phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with Cancermelanoma screened for the presence of KIT mutations and amplification between April 23 , 2007 , and April 16 , 2010 .
21642685
A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced Cancerunresectable melanoma arising from acral , mucosal , and chronically sun damaged sites .
21642685
CONCLUSIONS : Among patients with Canceradvanced melanoma harboring KIT alterations , treatment with imatinib mesylate results in significant clinical responses in a subset of patients .
21642685
Responses may be limited to Cancertumors harboring KIT alterations of proven functional relevance .
21642865
INTRODUCTION : This study compared the efficacy of pemetrexed in patients with Canceranaplastic lymphoma kinase ( ALK )-positive versus ALK negative ( epidermal growth factor receptor [ EGFR ] mutant or wild type [ WT ] for both ALK and EGFR ) non small cell lung cancer ( NSCLC ) .
21642865
INTRODUCTION : This study compared the efficacy of pemetrexed in patients with anaplastic lymphoma kinase ( ALK )-positive versus ALK negative ( epidermal growth factor receptor [ EGFR ] mutant or wild type [ WT ] for both ALK and EGFR ) Cancernon small cell lung cancer ( NSCLC ) .
21653686
The role of these molecular mechanisms for the responsiveness of Cancersquamous cell carcinoma of the head and neck ( SCCHN ) to cetuximab containing regimens remains unknown .
21653686
EXPERIMENTAL DESIGN : CancerTumor biopsies from 47 patients , enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel , were analyzed by immunohistochemistry for expression of EGFR , its deletion variant III ( EGFRvIII ) and its ligand amphiregulin ( AREG ) .
21653686
The relation between expression levels and Diseasedisease control rate ( DCR ) was evaluated by logistic regression .
21653686
Patients with high AREG expression in Cancertumor cells had significantly shortened OS ( HR : 2.2 , P = 0.002 ) and PFS ( HR 2.2 , P = 0.019 ) compared with patients with low expression score .
21663470
BACKGROUND : CancerHairy-cell leukemia ( HCL ) is a well defined clinicopathological entity whose underlying genetic lesion is still obscure .
21663470
Since BRAF V600E is oncogenic in Cancerother tumors , further analyses were focused on this genetic lesion .
21663470
None of the 195 patients with Cancerother peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant , including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias .
21663470
None of the 195 patients with other peripheral B-cell lymphomas or Cancerleukemias who were evaluated carried the BRAF V600E variant , including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias .
21663470
None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant , including 38 patients with Cancersplenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias .
21663470
None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant , including 38 patients with splenic marginal-zone lymphomas or Cancerunclassifiable splenic lymphomas or leukemias .
21663470
None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant , including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or Cancerleukemias .
21666749
BACKGROUND : CancerSquamous cell lung carcinomas account for approximately 25 % of new lung carcinoma cases and 40,000 deaths per year in the United States .
21666749
BACKGROUND : Squamous cell lung carcinomas account for approximately 25 % of Cancernew lung carcinoma cases and 40,000 deaths per year in the United States .
21666749
Although there are multiple genomically targeted therapies for Cancerlung adenocarcinoma , none has yet been reported in squamous cell lung carcinoma .
21666749
Although there are multiple genomically targeted therapies for lung adenocarcinoma , none has yet been reported in Cancersquamous cell lung carcinoma .
21666749
METHODOLOGY and PRINCIPAL FINDINGS : Using SNP array analysis , we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1 , LETM2 , and FGFR1-is amplified in 3 % of Cancerlung adenocarcinomas and 21 % of squamous cell lung carcinomas .
21666749
METHODOLOGY and PRINCIPAL FINDINGS : Using SNP array analysis , we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1 , LETM2 , and FGFR1-is amplified in 3 % of lung adenocarcinomas and 21 % of Cancersquamous cell lung carcinomas .
21666749
Furthermore , we demonstrated that a Cancernon small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth , as treatment of this cell line either with FGFR1 specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition .
21666749
CONCLUSIONS and SIGNIFICANCE : These studies show that FGFR1 amplification is common in Cancersquamous cell lung cancer , and that FGFR1 may represent a promising therapeutic target in non small cell lung cancer .
21666749
CONCLUSIONS and SIGNIFICANCE : These studies show that FGFR1 amplification is common in squamous cell lung cancer , and that FGFR1 may represent a promising therapeutic target in Cancernon small cell lung cancer .
21670202
The pathogenesis of Cancerchronic lymphocytic leukemia ( CLL ) , the most common leukemia in adults , is still largely unknown .
21670202
The pathogenesis of chronic lymphocytic leukemia ( CLL ) , the most Cancercommon leukemia in adults , is still largely unknown .
21670202
Although most of these genes were affected at low frequency in an expanded CLL screening cohort , mutational activation of NOTCH1 , observed in 8.3 % of CLL at diagnosis , was detected at significantly higher frequency during Diseasedisease progression toward Richter transformation ( 31.0 % ) , as well as in chemorefractory CLL ( 20.8 % ) .
21670202
Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the Diseasedisease , NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival .
21690468
PURPOSE : CancerMelanomas harbor aberrations in the c-Kit gene .
21690468
We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with Cancermetastatic melanoma harboring c-Kit mutations or amplifications .
21690468
PATIENTS AND METHODS : Forty-three patients with Cancermetastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial .
21690468
Each patient received a continuous dose of imatinib 400 mg/d unless Diseaseintolerable toxicities or disease progression occurred .
21690468
Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or Diseasedisease progression occurred .
21690468
Fifteen patients who experienced progression of Diseasedisease were allowed to escalate the dose to 800 mg/d .
21690468
Rate of Diseasetotal disease control was 53.5 % : 10 patients ( 23.3 % ; 95 % CI , 10.2 % to 36.4 % ) and 13 patients ( 30.2 % ; 95 % CI , 16.0 % to 44.4 % ) achieved partial response ( PR ) and stable disease ( SD ) , respectively .
21690468
Rate of total disease control was 53.5 % : 10 patients ( 23.3 % ; 95 % CI , 10.2 % to 36.4 % ) and 13 patients ( 30.2 % ; 95 % CI , 16.0 % to 44.4 % ) achieved partial response ( PR ) and Diseasestable disease ( SD ) , respectively .
21690468
Eighteen patients ( 41.9 % ) demonstrated regression of Cancertumor mass .
21690468
The median PFS and OS times for patients who had PR or SD versus Diseasedisease progression were 9.0 months versus 1.5 months ( P < .001 ) and 15.0 months versus 9.0 months ( P = .036 ) , respectively .
21690468
CONCLUSION : Imatinib demonstrated significant activity in patients with Cancermetastatic melanoma harboring genetic c-Kit aberrations , with an overall response rate of 23.3 % .
21690468
Escalation to 800 mg/d could not restore Diseasedisease control .
21716144
INTRODUCTION : Tyrosine kinase inhibitors ( TKIs ) targeted to MET are undergoing clinical trials in patients with Cancersolid tumors , but the precise mechanism of the antitumor activity of these drugs remains unclear .
21716144
We examined the antitumor action of the MET TKI crizotinib ( PF-02341066 ) in Cancerlung cancer cells that are positive or negative for MET amplification or mutation .
21716144
METHODS : The antitumor action of crizotinib was evaluated on the basis of signal transduction , cell proliferation , apoptosis , and progression of Cancertumor xenografts .
21716144
RESULTS : Inhibition of MET signaling by crizotinib or by RNA interference mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal regulated kinase phosphorylation in Cancerlung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET .
21716144
CONCLUSIONS : Crizotinib shows a marked antitumor action in CancerMET amplification positive lung cancer cells but not in cells without MET amplification , including those with a MET mutation .
21730982
BACKGROUND : The aim of this study was to investigate the patterns of epidermal growth factor receptor ( EGFR ) overexpression , EGFR gene amplification , and the presence of activating mutations in the tyrosine kinase domain of this gene in Cancersquamous cell carcinomas and adenocarcinomas and adenosquamous carcinomas of the uterine cervix .
21730982
BACKGROUND : The aim of this study was to investigate the patterns of epidermal growth factor receptor ( EGFR ) overexpression , EGFR gene amplification , and the presence of activating mutations in the tyrosine kinase domain of this gene in squamous cell carcinomas and Canceradenocarcinomas and adenosquamous carcinomas of the uterine cervix .
21730982
BACKGROUND : The aim of this study was to investigate the patterns of epidermal growth factor receptor ( EGFR ) overexpression , EGFR gene amplification , and the presence of activating mutations in the tyrosine kinase domain of this gene in squamous cell carcinomas and adenocarcinomas and Canceradenosquamous carcinomas of the uterine cervix .
21730982
METHODS : The EGFR expression , amplification , and mutation in Cancercervical carcinomas were assessed by immunohistochemistry , fluorescence in situ hybridisation , and PCR-SSCP , respectively , and correlated with clinical data collected by a retrospective chart review .
21730982
A functional assessment was performed by inactivating EGFR in Cancercervical cancer cells with the potent inhibitor AG1478 .
21730982
RESULTS : Immunohistochemical analysis revealed that 6 out of 59 ( 10.2 % ) Cancercervical squamous cell carcinomas showed significant amplification of the EGFR locus , whereas none of the 52 adeno and adenosquamous cell carcinomas had detectable EGFR amplification ( P < 0.05 ) .
21730982
RESULTS : Immunohistochemical analysis revealed that 6 out of 59 ( 10.2 % ) cervical squamous cell carcinomas showed significant amplification of the EGFR locus , whereas none of the 52 adeno and Canceradenosquamous cell carcinomas had detectable EGFR amplification ( P < 0.05 ) .
21730982
The EGFR amplification significantly correlated with shorter overall survival ( P = 0.001 ) in Cancercervical squamous cell carcinomas .
21730982
None of the Cancersquamous cell carcinomas ( 0 % : 0 out of 32 ) had detectable oncogenic mutations in EGFR exons 18 through 21 .
21730982
The frequencies of KRAS and BRAF mutations were very low in both squamous and adeno and Canceradenosquamous cell carcinomas .
21730982
Sensitivity of Cancercervical cancer cells to AG1478 depended on the presence of EGFR overexpression .
21730982
AG1478 induced EGFR inactivation in cell lines with EGFR overexpression significantly suppressed Cancertumour development and progression in a mouse xenograft model .
21730982
CONCLUSION : Our data suggest that EGFR signalling is important in a subset of Cancercervical squamous cell carcinomas and that anti-EGFR therapy may benefit patients who carry the 7p11 .2 amplicon in their tumours .
21730982
CONCLUSION : Our data suggest that EGFR signalling is important in a subset of cervical squamous cell carcinomas and that anti-EGFR therapy may benefit patients who carry the 7p11 .2 amplicon in their Cancertumours .
21732342
The epidermal growth factor receptor ( EGFR ) family of receptor tyrosine kinases has been implicated in a variety of Cancercancers .
21732342
In particular , activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in Cancernon small cell lung cancer ( NSCLC ) patients .
21732342
Additionally , HM781-36B shows an excellent efficacy in a variety of EGFR- and CancerHER-2-dependent tumor xenograft models , including erlotinib sensitive HCC827 NSCLC cells , erlotinib resistant NCI-H1975 NSCLC cells , HER-2 overexpressing Calu-3 NSCLC cells , NCI-N87 gastric cancer cells , SK-Ov3 ovarian cancer cells and EGFR overexpressing A431 epidermoid carcinoma cancer cells .
21732342
Additionally , HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models , including erlotinib sensitive HCC827 NSCLC cells , erlotinib resistant NCI-H1975 NSCLC cells , HER-2 overexpressing Calu-3 NSCLC cells , CancerNCI-N87 gastric cancer cells , SK-Ov3 ovarian cancer cells and EGFR overexpressing A431 epidermoid carcinoma cancer cells .
21732342
Additionally , HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models , including erlotinib sensitive HCC827 NSCLC cells , erlotinib resistant NCI-H1975 NSCLC cells , HER-2 overexpressing Calu-3 NSCLC cells , NCI-N87 gastric cancer cells , CancerSK-Ov3 ovarian cancer cells and EGFR overexpressing A431 epidermoid carcinoma cancer cells .
21732342
Additionally , HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models , including erlotinib sensitive HCC827 NSCLC cells , erlotinib resistant NCI-H1975 NSCLC cells , HER-2 overexpressing Calu-3 NSCLC cells , NCI-N87 gastric cancer cells , SK-Ov3 ovarian cancer cells and EGFR overexpressing CancerA431 epidermoid carcinoma cancer cells .
21732342
On the basis of these preclinical results , HM781-36B is the most potent pan-HER inhibitor , which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation ( EGFR T790M ) , Cancerbreast cancer and gastric cancer .
21732342
On the basis of these preclinical results , HM781-36B is the most potent pan-HER inhibitor , which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation ( EGFR T790M ) , breast cancer and Cancergastric cancer .
21747090
PURPOSE : In the clinical management of children with relapsed Canceracute lymphoblastic leukemia ( ALL ) , treatment resistance remains a major challenge .
21747090
PATIENTS AND METHODS : Therefore , we systematically studied 265 first-relapse patients enrolled in the CancerGerman Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Mu nster 2002 ( ALL-REZ BFM 2002 ) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation dependent probe amplification .
21747090
CONCLUSION : Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL , in which they independently predict AdverseOutcomehigh risk of treatment failure in a significant number of patients .
21747090
Therefore , they will aid in AdverseOutcomefuture risk assessment of children with ALL relapse .
21791641
CancerAnaplastic lymphoma kinase ( ALK ) tyrosine kinase inhibitors ( TKI ) , including crizotinib , are effective treatments in preclinical models and in cancer patients with ALK translocated cancers .
21791641
Anaplastic lymphoma kinase ( ALK ) tyrosine kinase inhibitors ( TKI ) , including crizotinib , are effective treatments in preclinical models and in Cancercancer patients with ALK translocated cancers .
21791641
Anaplastic lymphoma kinase ( ALK ) tyrosine kinase inhibitors ( TKI ) , including crizotinib , are effective treatments in preclinical models and in cancer patients with ALK translocated Cancercancers .
21791641
Here we report two mechanisms of ALK TKI resistance identified from a crizotinib treated Cancernon small cell lung cancer ( NSCLC ) patient and in a cell line generated from the resistant tumor ( DFCI076 ) as well as from studying a resistant version of the ALK TKI ( TAE684 )-sensitive H3122 cell line .
21791641
Here we report two mechanisms of ALK TKI resistance identified from a crizotinib treated non small cell lung cancer ( NSCLC ) patient and in a cell line generated from the Cancerresistant tumor ( DFCI076 ) as well as from studying a resistant version of the ALK TKI ( TAE684 )-sensitive H3122 cell line .
21791641
These mechanisms can occur independently , or in the Cancersame cancer , suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients .
21796119
CancerFollicular lymphoma ( FL ) and diffuse large B-cell lymphoma ( DLBCL ) are the two most common non Hodgkin lymphomas ( NHLs ) .
21796119
Follicular lymphoma ( FL ) and Cancerdiffuse large B-cell lymphoma ( DLBCL ) are the two most common non Hodgkin lymphomas ( NHLs ) .
21796119
Follicular lymphoma ( FL ) and diffuse large B-cell lymphoma ( DLBCL ) are the two most Cancercommon non Hodgkin lymphomas ( NHLs ) .
21796119
Here we sequenced Cancertumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL .
21796119
We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations , and then Cancerre-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations .
21828143
The studies concerning clinical implications of TET2 mutation in patients with Cancerprimary acute myeloid leukemia ( AML ) are scarce .
21828143
In conclusion , TET2 mutation is associated with AdverseOutcomepoor prognosis in AML patients with intermediate-risk cytogenetics , especially when it is combined with other adverse molecular markers .
21828143
TET2 mutation appeared to be unstable during Diseasedisease evolution .
21840482
HER2 kinase inhibitors , such as lapatinib , have demonstrated clinical efficacy in HER2 amplified Cancerbreast cancers .
21840482
By profiling nearly 700 Cancerhuman cancer cell lines , we identified a subset of non HER2 amplified cancer cells with striking sensitivity to HER2 kinase inhibition-particularly from head and neck tumors .
21840482
By profiling nearly 700 human cancer cell lines , we identified a subset of non HER2 amplified Cancercancer cells with striking sensitivity to HER2 kinase inhibition-particularly from head and neck tumors .
21840482
By profiling nearly 700 human cancer cell lines , we identified a subset of non HER2 amplified cancer cells with striking sensitivity to HER2 kinase inhibition-particularly from head and Cancerneck tumors .
21840482
Elevated NRG1 expression and activated HER3 are strongly associated with lapatinib sensitivity invitro , and these biomarkers were enriched in a subset of primary head and Cancerneck cancer samples .
21840482
The findings suggest that patients with NRG1 driven Cancertumors lacking HER2 amplification may derive significant clinical benefit from HER2 : HER3 directed therapies .
21847063
INTRODUCTION : KRAS mutations are present in 30 % of Cancerlung adenocarcinomas .
21847063
This phase II study determined the activity of salirasib in patients with Canceradvanced lung adenocarcinomas with KRAS mutations .
21847063
METHODS : Two cohorts of patients with Cancerstage IIIB/IV lung adenocarcinoma were eligible : patients with tumors with KRAS mutations who were previously treated with chemotherapy and patients receiving initial therapy who had > = 15 pack-year smoking history .
21847063
METHODS : Two cohorts of patients with stage IIIB/IV lung adenocarcinoma were eligible : patients with Cancertumors with KRAS mutations who were previously treated with chemotherapy and patients receiving initial therapy who had > = 15 pack-year smoking history .
21847063
Of the previously treated patients , 7 of 23 ( 30 % ) had Diseasestable disease at 10 weeks , and 4 of 10 ( 40 % ) previously untreated patients had stable disease at 10 weeks .
21847063
Of the previously treated patients , 7 of 23 ( 30 % ) had stable disease at 10 weeks , and 4 of 10 ( 40 % ) previously untreated patients had Diseasestable disease at 10 weeks .
21847063
Diarrhea , nausea , and fatigue were the most Diseasecommon toxicities .
21847063
CONCLUSIONS : Salirasib at the current dose and schedule has insufficient activity in the treatment of CancerKRAS mutant lung adenocarcinoma to warrant further evaluation .
21847063
The successful enrollment of 30 patients with Cancertumors with KRAS mutant lung adenocarcinoma over 15 months at a single site demonstrates that drug trials directed at a KRAS specific genotype in lung cancer are feasible .
21847063
The successful enrollment of 30 patients with tumors with CancerKRAS mutant lung adenocarcinoma over 15 months at a single site demonstrates that drug trials directed at a KRAS specific genotype in lung cancer are feasible .
21847063
The successful enrollment of 30 patients with tumors with KRAS mutant lung adenocarcinoma over 15 months at a single site demonstrates that drug trials directed at a KRAS specific genotype in Cancerlung cancer are feasible .
21862407
We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with Canceradvanced triple negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer .
21862407
We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple negative breast cancer or high-grade serous and/or Cancerundifferentiated ovarian cancer .
21862407
METHODS : In this phase 2 , multicentre , open-label , non randomised study , women with advanced high-grade serous and/or Cancerundifferentiated ovarian carcinoma or triple negative breast cancer were enrolled and received olaparib 400 mg twice a day .
21862407
METHODS : In this phase 2 , multicentre , open-label , non randomised study , women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or Cancertriple negative breast cancer were enrolled and received olaparib 400 mg twice a day .
21862407
The primary endpoint was objective response rate by Response Evaluation Criteria In CancerSolid Tumors ( RECIST ) .
21862407
FINDINGS : 91 patients were enrolled ( 65 with Cancerovarian cancer and 26 breast cancer ) and 90 were treated between July 8 , 2008 , and Sept 24 , 2009 .
21862407
FINDINGS : 91 patients were enrolled ( 65 with ovarian cancer and 26 Cancerbreast cancer ) and 90 were treated between July 8 , 2008 , and Sept 24 , 2009 .
21862407
In the Cancerovarian cancer cohorts , 64 patients received treatment .
21862407
No confirmed objective responses were reported in patients with Cancerbreast cancer .
21862407
The most common adverse events were fatigue ( 45 [ 70 % ] of patients with Cancerovarian cancer , 13 [ 50 % ] of patients with breast cancer ) , nausea ( 42 [ 66 % ] and 16 [ 62 % ] ) , vomiting ( 25 [ 39 % ] and nine [ 35 % ] ) , and decreased appetite ( 23 [ 36 % ] and seven [ 27 % ] ) .
21862407
The most common adverse events were fatigue ( 45 [ 70 % ] of patients with ovarian cancer , 13 [ 50 % ] of patients with Cancerbreast cancer ) , nausea ( 42 [ 66 % ] and 16 [ 62 % ] ) , vomiting ( 25 [ 39 % ] and nine [ 35 % ] ) , and decreased appetite ( 23 [ 36 % ] and seven [ 27 % ] ) .
21862407
INTERPRETATION : Our study suggests that olaparib is a promising treatment for women with Cancerovarian cancer and further assessment of the drug in clinical trials is needed .
21862683
Although erlotinib has become an important therapeutic option in addition to gemcitabine , the high frequency of KRAS mutations in Cancerpancreatic cancer probably limits the benefits .
21862683
We retrospectively studied 136 Cancerpancreatic cancer patients with available formalin fixed paraffin embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine based chemotherapy .
21862683
We retrospectively studied 136 pancreatic cancer patients with available formalin fixed Cancerparaffin embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine based chemotherapy .
21862683
We retrospectively studied 136 pancreatic cancer patients with available formalin fixed paraffin embedded tumor blocks from 2003 to 2009 to understand the clinical significance of KRAS mutations in Cancerpancreatic cancer patients treated with gemcitabine based chemotherapy .
21862683
In this study , 71 ( 52.2 % ) of the 136 Cancerpancreatic adenocarcinomas examined harbored a point mutation in codons 12 ( n = 70 ) and 61 ( n = 1 ) of KRAS .
21862683
Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology ( P < 0.001 ; HR = 0.437 , 95 % CI : 0.301-0 .634 ) , locally advanced Diseasedisease ( P < 0.001 ; HR = 0.417 , 95 % CI : 0.255-0 .681 ) , response to first-line chemotherapy ( P = 0.003 ; HR = 0.482 , 95 % CI : 0.297-0 .780 ) , and wild-type KRAS ( P = 0.001 ; HR = 0.523 , 95 % CI : 0.355-0 .770 ) .
21862683
These results need to be further explored in upcoming prospective studies to provide a rationale for personalized medicine in Cancerpancreatic cancer .
21883677
A panel of 17 Cancernon small cell lung cancer ( NSCLC ) cell lines was used to investigate whether alterations in the ABCB1 gene or its mRNA expression correlated with in vitro chemosensitivity to paclitaxel .
21890455
PURPOSE : K-Ras somatic mutations are a strong predictive biomarker for resistance to epidermal growth factor receptor ( EGFR ) inhibitors in patients with colorectal and Cancerpancreatic cancer .
21890455
We previously showed that the novel Toll like receptor 9 ( TLR9 ) agonist immunomodulatory oligonucleotide ( IMO ) has a strong in vivo activity in Cancercolorectal cancer models by interfering with EGFR related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab .
21890455
EXPERIMENTAL DESIGN : In the present study , we investigated , both in vitro and in vivo , the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and Cancerorthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors .
21890455
RESULTS : We showed that IMO was able to significantly restore the sensitivity of CancerK-Ras mutant cancer cells to cetuximab , producing a marked inhibition of cell survival and a complete suppression of mitogen activated protein kinase phosphorylation , when used in combination with cetuximab .
21890455
In vivo , IMO plus cetuximab combination caused a potent and long lasting cooperative antitumor activity in CancerLS174T colorectal cancer and in orthotopic AsPC1 pancreatic cancer .
21890455
In vivo , IMO plus cetuximab combination caused a potent and long lasting cooperative antitumor activity in LS174T colorectal cancer and in Cancerorthotopic AsPC1 pancreatic cancer .
21890455
The capability of IMO to restore cetuximab sensitivity was further confirmed by using CancerK-Ras mutant colorectal cancer cell models obtained through homologous recombination technology .
21890455
CONCLUSIONS : We showed that IMO markedly inhibits growth of K-Ras mutant colon and Cancerpancreatic cancers in vitro and in nude mice and cooperates with cetuximab via multiple mechanisms of action .
21890455
Therefore , we propose IMO plus cetuximab as a therapeutic strategy for K-Ras wild-type as well for K-Ras mutant , cetuximab resistant colorectal and Cancerpancreatic cancers .
21900593
Cetuximab , an antibody directed against the epidermal growth factor receptor , is an effective clinical therapy for patients with colorectal , head and neck , and Cancernon small cell lung cancer , particularly for those with KRAS and BRAF wild-type cancers .
21900593
Cetuximab , an antibody directed against the epidermal growth factor receptor , is an effective clinical therapy for patients with colorectal , head and neck , and non small cell lung cancer , particularly for those with KRAS and CancerBRAF wild-type cancers .
21900593
A subset of Cancercolorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab based therapy has ERBB2 amplification or high levels of circulating heregulin .
21900593
Moreover , these results suggest that ERBB2 inhibitors , in combination with cetuximab , represent a rational therapeutic strategy that should be assessed in patients with Cancercetuximab resistant cancers .
21920589
OBJECTIVES : We investigated the relationship between BRCA1 protein expression by immunohistochemistry ( IHC ) and clinical outcome following platinum and platinum and taxane chemotherapy in Cancersporadic epithelial ovarian cancer ( EOC ) .
21920589
METHODS : BRCA1 IHC was performed on a cohort of 292 Cancerovarian tumours from two UK oncology centres .
21926398
BACKGROUND : Despite therapeutic innovations , Cancermetastatic colorectal cancer ( mCRC ) is still characterized by poor prognosis and few molecular markers predict the risk of progression .
21926398
BACKGROUND : Despite therapeutic innovations , metastatic colorectal cancer ( mCRC ) is still characterized by AdverseOutcomepoor prognosis and few molecular markers predict the risk of progression .
21926398
BACKGROUND : Despite therapeutic innovations , metastatic colorectal cancer ( mCRC ) is still characterized by poor prognosis and few molecular markers predict the AdverseOutcomerisk of progression .
21926398
In Cancercolorectal cancer ( CRC ) , EZH2 overexpression predicts shorter survival .
21933749
BACKGROUND : ALK gene rearrangement defines a new molecular subtype of Cancernon-small-cell lung cancer ( NSCLC ) .
21948233
PURPOSE : EML4-ALK fusions define a subset of Cancerlung cancers that can be effectively treated with anaplastic lymphoma kinase ( ALK ) inhibitors .
21948233
PURPOSE : EML4-ALK fusions define a subset of lung cancers that can be effectively treated with Canceranaplastic lymphoma kinase ( ALK ) inhibitors .
21948233
Thus , a better understanding of resistance mechanisms will help to enhance Cancertumor control in EML4-ALK-positive tumors .
21948233
Thus , a better understanding of resistance mechanisms will help to enhance tumor control in CancerEML4-ALK-positive tumors .
21948233
An independent resistance screen in CancerALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066 .
21964527
INTRODUCTION : Amrubicin is a promising agent in the treatment of Cancerlung cancer , but predictive biomarkers have not yet been described .
21964527
METHODS : Gene and protein expression of NQO1 , amrubicinol cytotoxicity , and C609T single-nucleotide polymorphism of NQO1 were evaluated in 29 Cancerlung cancer cell lines : 14 small cell lung cancer ( SCLC ) and 15 non SCLC ( NSCLC ) .
21964527
METHODS : Gene and protein expression of NQO1 , amrubicinol cytotoxicity , and C609T single-nucleotide polymorphism of NQO1 were evaluated in 29 lung cancer cell lines : 14 Cancersmall cell lung cancer ( SCLC ) and 15 non SCLC ( NSCLC ) .
21985784
Therapies inhibiting receptor tyrosine kinases ( RTKs ) are effective against some Cancerhuman cancers when they lead to simultaneous downregulation of PI3K and AKT and MEK and ERK signaling .
21985784
However , mutant KRAS has the capacity to directly activate ERK and PI3K signaling , and this is thought to underlie the resistance of CancerKRAS mutant cancers to RTK inhibitors .
21985784
Here , we have elucidated the molecular regulation of both the PI3K and AKT and MEK and ERK signaling pathways in CancerKRAS mutant colorectal cancer cells and identified combination therapies that lead to robust cancer cell apoptosis .
21985784
Here , we have elucidated the molecular regulation of both the PI3K and AKT and MEK and ERK signaling pathways in KRAS mutant colorectal cancer cells and identified combination therapies that lead to Cancerrobust cancer cell apoptosis .
21985784
KRAS knockdown using shRNA suppressed ERK signaling in all of the Cancerhuman KRAS mutant colorectal cancer cell lines examined .
21985784
Interestingly , combination of RTK and MEK inhibitors led to concomitant inhibition of PI3K and MEK signaling , marked growth suppression , and robust apoptosis of Cancerhuman KRAS mutant colorectal cancer cell lines in vitro and upon xenografting in mice .
21985784
These findings provide a framework for utilizing RTK inhibitors in the treatment of CancerKRAS mutant colorectal cancers .
21995386
BACKGROUND : DiseaseMyelodysplastic syndromes are a diverse and common group of chronic hematologic cancers .
21995386
BACKGROUND : Myelodysplastic syndromes are a diverse and common group of Cancerchronic hematologic cancers .
21995386
Targeted resequencing of the gene encoding RNA splicing factor 3B , subunit 1 ( SF3B1 ) , was also performed in a cohort of 2087 patients with myeloid or Cancerother cancers .
21995386
Follow-up revealed SF3B1 mutations in 72 of 354 patients ( 20 % ) with Diseasemyelodysplastic syndromes , with particularly high frequency among patients whose disease was characterized by ring sideroblasts ( 53 of 82 [ 65 % ] ) .
21995386
Follow-up revealed SF3B1 mutations in 72 of 354 patients ( 20 % ) with myelodysplastic syndromes , with particularly high frequency among patients whose Diseasedisease was characterized by ring sideroblasts ( 53 of 82 [ 65 % ] ) .
21995386
The gene was also mutated in 1 to 5 % of patients with a variety of Cancerother tumor types .
21995386
Clinically , patients with SF3B1 mutations had Diseasefewer cytopenias and longer event-free survival than patients without SF3B1 mutations .
21995386
CONCLUSIONS : Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of Diseasemyelodysplastic syndromes .
21997850
The somatic mutations of isocitrate dehydrogenase genes ( IDH1 and IDH2 ) have been identified in a proportion of Cancerhematologic malignancies .
21997850
We examined IDH1 R132 and IDH2 R140 and R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with Cancerdifferent myeloid malignancies including 198 acute myeloid leukemia ( AML ) , 82 myelodysplastic syndrome ( MDS ) , 85 chronic myeloid leukemia , and 57 myeloproliferative neoplasms .
21997850
We examined IDH1 R132 and IDH2 R140 and R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with different myeloid malignancies including 198 Canceracute myeloid leukemia ( AML ) , 82 myelodysplastic syndrome ( MDS ) , 85 chronic myeloid leukemia , and 57 myeloproliferative neoplasms .
21997850
We examined IDH1 R132 and IDH2 R140 and R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with different myeloid malignancies including 198 acute myeloid leukemia ( AML ) , 82 Diseasemyelodysplastic syndrome ( MDS ) , 85 chronic myeloid leukemia , and 57 myeloproliferative neoplasms .
21997850
We examined IDH1 R132 and IDH2 R140 and R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with different myeloid malignancies including 198 acute myeloid leukemia ( AML ) , 82 myelodysplastic syndrome ( MDS ) , 85 Cancerchronic myeloid leukemia , and 57 myeloproliferative neoplasms .
22004109
A role of heat shock protein 27 ( HSP27 ) as a potential biomarker has been reported in Cancervarious tumour entities , but comprehensive studies in pancreatic cancer are lacking .
22004109
A role of heat shock protein 27 ( HSP27 ) as a potential biomarker has been reported in various tumour entities , but comprehensive studies in Cancerpancreatic cancer are lacking .
22004109
Applying tissue microarray ( TMA ) analysis , we correlated HSP27 protein expression status with clinicopathologic parameters in Cancerpancreatic ductal adenocarcinoma specimens from 86 patients .
22004109
Complementary , we established HSP27 overexpression and RNA-interference models to assess the impact of HSP27 on chemo- and radiosensitivity directly in Cancerpancreatic cancer cells .
22004109
In the TMA study , HSP27 expression was found in 49 % of Cancertumour samples .
22004109
HSP27 expression also correlated inversely with nuclear p53 accumulation , indicating either protein interactions between HSP27 and p53 or TP53 mutation dependent HSP27 regulation in Cancerpancreatic cancer .
22004109
In the sensitivity studies , HSP27 overexpression rendered HSP27 low expressing CancerPL5 pancreatic cancer cells more susceptible towards treatment with gemcitabine .
22004109
Importantly , HSP27 expression was inducible in Cancerpancreatic cancer cell lines as well as primary cells .
22004109
Taken together , our study suggests a role for HSP27 as a prognostic and predictive marker in Cancerpancreatic cancer .
22004109
Additional studies need to clarify whether modulation of HSP27 expression could represent an attractive concept to support the incorporation of hyperthermia in clinical treatment protocols for Cancerpancreatic cancer .
22025163
PURPOSE : AKT signaling is frequently deregulated in Cancerhuman cancers .
22025163
PATIENTS AND METHODS : Patients with Canceradvanced solid tumors received MK-2206 on alternate days .
22025163
CancerPaired tumor biopsies were mandated at the MTD for biomarker studies .
22025163
PD studies incorporated Cancertumor and hair follicle analyses , and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog ( PTEN ) loss .
22025163
PD studies incorporated tumor and hair follicle analyses , and putative predictive biomarker studies included Cancertumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog ( PTEN ) loss .
22025163
Dose limiting Diseasetoxicities included skin rash and stomatitis , establishing the MTD at 60 mg .
22025163
Dose limiting toxicities included skin rash and Diseasestomatitis , establishing the MTD at 60 mg .
22025163
DiseaseDrug related toxicities included skin rash ( 51.5 % ) , nausea ( 36.4 % ) , pruritus ( 24.2 % ) , hyperglycemia ( 21.2 % ) , and diarrhea ( 21.2 % ) .
22025163
Drug related toxicities included skin rash ( 51.5 % ) , nausea ( 36.4 % ) , pruritus ( 24.2 % ) , Diseasehyperglycemia ( 21.2 % ) , and diarrhea ( 21.2 % ) .
22025163
Phosphorylated serine 473 AKT declined in all Cancertumor biopsies assessed ( P = .015 ) , and phosphorylated threonine 246 proline rich AKT substrate 40 was suppressed in hair follicles at 6 hours ( P = .008 ) , on days 7 ( P = .028 ) and 15 ( P = .025 ) with MK-2206 ; reversible hyperglycemia and increases in insulin c-peptide were also observed , confirming target modulation .
22025163
Phosphorylated serine 473 AKT declined in all tumor biopsies assessed ( P = .015 ) , and phosphorylated threonine 246 proline rich AKT substrate 40 was suppressed in hair follicles at 6 hours ( P = .008 ) , on days 7 ( P = .028 ) and 15 ( P = .025 ) with MK-2206 ; Diseasereversible hyperglycemia and increases in insulin c-peptide were also observed , confirming target modulation .
22025163
A patient with Cancerpancreatic adenocarcinoma ( PTEN loss ; KRAS G12D mutation ) treated at 60 mg on alternate days experienced a decrease of approximately 60 % in cancer antigen 19-9 levels and 23 % shrinkage in tumor measurements .
22025163
A patient with pancreatic adenocarcinoma ( PTEN loss ; KRAS G12D mutation ) treated at 60 mg on alternate days experienced a decrease of approximately 60 % in Cancercancer antigen 19-9 levels and 23 % shrinkage in tumor measurements .
22025163
A patient with pancreatic adenocarcinoma ( PTEN loss ; KRAS G12D mutation ) treated at 60 mg on alternate days experienced a decrease of approximately 60 % in cancer antigen 19-9 levels and 23 % shrinkage in Cancertumor measurements .
22025163
Two patients with Cancerpancreatic neuroendocrine tumors had minor tumor responses .
22025163
Two patients with pancreatic neuroendocrine tumors had Cancerminor tumor responses .
22031865
The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics , outcomes , and gene- and microRNA-expression profiles in primary cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) are unknown .
22033490
Unlike the case with Canceracute myeloid leukemia , there is limited information on the prognostic impact of isocitrate dehydrogenase ( IDH ) mutations in myelodysplastic syndromes ( MDS ) .
22033490
Unlike the case with acute myeloid leukemia , there is limited information on the prognostic impact of isocitrate dehydrogenase ( IDH ) mutations in Diseasemyelodysplastic syndromes ( MDS ) .
22033490
Mutational frequency was 4 % ( 2 of 56 ) in Diseaserefractory anemia with ring sideroblasts , 12 % ( 16 of 130 ) in refractory cytopenia with multilineage dysplasia , 14 % ( 2 of 14 ) in MDS-unclassifiable , 14 % ( 6 of 42 ) in refractory anemia with excess blasts ( RAEB ) -1 and 23 % ( 8 of 35 ) in RAEB-2 .
22033490
Mutational frequency was 4 % ( 2 of 56 ) in refractory anemia with ring sideroblasts , 12 % ( 16 of 130 ) in Diseaserefractory cytopenia with multilineage dysplasia , 14 % ( 2 of 14 ) in MDS-unclassifiable , 14 % ( 6 of 42 ) in refractory anemia with excess blasts ( RAEB ) -1 and 23 % ( 8 of 35 ) in RAEB-2 .
22033490
Mutational frequency was 4 % ( 2 of 56 ) in refractory anemia with ring sideroblasts , 12 % ( 16 of 130 ) in refractory cytopenia with multilineage dysplasia , 14 % ( 2 of 14 ) in MDS-unclassifiable , 14 % ( 6 of 42 ) in Diseaserefractory anemia with excess blasts ( RAEB ) -1 and 23 % ( 8 of 35 ) in RAEB-2 .
22033490
Multivariable analysis identified presence of mutant IDH1 ( P = 0.0004 ; hazard ration 4.0 , 95 % confidence interval 1.9-8 .8 ) , revised International Prognostic Scoring System AdverseOutcomerisk category ( P < 0.0001 ) , and red cell transfusion need ( P = 0.002 ) as independent predictors of inferior survival .
22034911
Activating gene rearrangements of Canceranaplastic lymphoma kinase ( ALK ) have been identified as driver mutations in non-small-cell lung cancer , inflammatory myofibroblastic tumors , and other cancers .
22034911
Activating gene rearrangements of anaplastic lymphoma kinase ( ALK ) have been identified as driver mutations in Cancernon-small-cell lung cancer , inflammatory myofibroblastic tumors , and other cancers .
22034911
Activating gene rearrangements of anaplastic lymphoma kinase ( ALK ) have been identified as driver mutations in non-small-cell lung cancer , Cancerinflammatory myofibroblastic tumors , and other cancers .
22034911
Activating gene rearrangements of anaplastic lymphoma kinase ( ALK ) have been identified as driver mutations in non-small-cell lung cancer , inflammatory myofibroblastic tumors , and Cancerother cancers .
22034911
Crizotinib , a dual MET and ALK inhibitor , has demonstrated promising clinical activity in patients with Cancernon-small-cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations .
22034911
Crizotinib , a dual MET and ALK inhibitor , has demonstrated promising clinical activity in patients with non-small-cell lung cancer and Cancerinflammatory myofibroblastic tumors harboring ALK translocations .
22034911
In separate studies , we demonstrated that crizotinib has relatively modest potency in CancerALK positive non-small-cell lung cancer cell lines .
22038994
PURPOSE : Metastasis is responsible for the death of Cancermost cancer patients , yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis .
22038994
PURPOSE : Metastasis is responsible for the death of most cancer patients , yet few therapeutic agents are available which specifically target the molecular events that lead to Cancermetastasis .
22038994
We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in Canceruveal melanoma ( UM ) and metastasis .
22038994
We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma ( UM ) and Cancermetastasis .
22038994
VPA inhibited the growth of CancerUM tumors in vivo .
22038994
CONCLUSIONS : These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of Diseasemicrometastatic disease in UM .
22046346
BACKGROUND : Overexpression of the ERBB2 kinase is observed in about one-third of Cancerbreast cancer patients and the dual ERBB1 and ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2 positive breast cancer .
22046346
BACKGROUND : Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1 and ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of Canceradvanced ERBB2 positive breast cancer .
22046346
Mutations in the ERBB2 receptor have recently been reported in Cancerbreast cancer at diagnosis and also in gastric , colorectal and lung cancer .
22046346
Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric , colorectal and Cancerlung cancer .
22046346
These mutations may have an impact on the clinical responses achieved with lapatinib in Cancerbreast cancer and may also have a potential impact on the use of lapatinib in other solid cancers .
22046346
These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in Cancerother solid cancers .
22046346
Irreversible ERBB2 inhibitors may offer alternative treatment options for Cancerbreast cancer and other solid tumor patients harbouring lapatinib resistance mutations .
22046346
Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and Cancerother solid tumor patients harbouring lapatinib resistance mutations .
22056021
BACKGROUND : Findings from the phase 3 First-Line ErbituX in Cancerlung cancer ( FLEX ) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone ( hazard ratio [ HR ] 0.871 , 95 % CI 0.762-0 .996 ; p = 0.044 ) in patients with advanced non-small-cell lung cancer ( NSCLC ) .
22056021
BACKGROUND : Findings from the phase 3 First-Line ErbituX in lung cancer ( FLEX ) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone ( hazard ratio [ HR ] 0.871 , 95 % CI 0.762-0 .996 ; p = 0.044 ) in patients with Canceradvanced non-small-cell lung cancer ( NSCLC ) .
22056021
To define patients benefiting most from cetuximab , we studied the association of Cancertumour EGFR expression level with clinical outcome in FLEX study patients .
22056021
METHODS : We used prospectively collected Cancertumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300 .
22056021
Treatment outcome was analysed in patients with low ( immunohistochemistry score < 200 ) and high ( > = 200 ) Cancertumour EGFR expression .
22056021
FINDINGS : CancerTumour EGFR immunohistochemistry data were available for 1121 of 1125 ( 99.6 % ) patients from the FLEX study ITT population .
22056021
INTERPRETATION : High EGFR expression is a Cancertumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC .
22072639
Activating mutations in the Canceranaplastic lymphoma kinase ( ALK ) gene were recently discovered in neuroblastoma , a cancer of the developing autonomic nervous system that is the most commonly diagnosed malignancy in the first year of life .
22072639
Activating mutations in the anaplastic lymphoma kinase ( ALK ) gene were recently discovered in Cancerneuroblastoma , a cancer of the developing autonomic nervous system that is the most commonly diagnosed malignancy in the first year of life .
22072639
Activating mutations in the anaplastic lymphoma kinase ( ALK ) gene were recently discovered in neuroblastoma , a Cancercancer of the developing autonomic nervous system that is the most commonly diagnosed malignancy in the first year of life .
22072639
Activating mutations in the anaplastic lymphoma kinase ( ALK ) gene were recently discovered in neuroblastoma , a cancer of the developing autonomic nervous system that is the most commonly diagnosed Cancermalignancy in the first year of life .
22072639
The most frequent ALK mutations in Cancerneuroblastoma cause amino acid substitutions ( F1174L and R1275Q ) in the intracellular tyrosine kinase domain of the intact ALK receptor .
22072639
Identification of ALK as an oncogenic driver in Cancerneuroblastoma suggests that crizotinib ( PF-02341066 ) , a dual specific inhibitor of the ALK and Met tyrosine kinases , will be useful in treating this malignancy .
22072639
Identification of ALK as an oncogenic driver in neuroblastoma suggests that crizotinib ( PF-02341066 ) , a dual specific inhibitor of the ALK and Met tyrosine kinases , will be useful in treating this Cancermalignancy .
22072639
Here , we assessed the ability of crizotinib to inhibit proliferation of Cancerneuroblastoma cell lines and xenografts expressing mutated or wild-type ALK .
22077063
Analysis of the Cancerchronic lymphocytic leukemia ( CLL ) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation .
22077063
The AdverseOutcomepoor prognosis conferred by NOTCH1 mutations was attributable , at least in part , to shorter treatment-free survival and higher risk of Richter transformation .
22077063
The poor prognosis conferred by NOTCH1 mutations was attributable , at least in part , to shorter treatment-free survival and higher AdverseOutcomerisk of Richter transformation .
22081665
Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with Canceracute myeloid leukemia .
22081665
To assess their prognostic significance , we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding Canceracute promyelocytic leukemia , aged from 18 to 65 years and treated in Toulouse University Hospital .
22090360
PURPOSE : AdverseOutcomeMortality of patients with head and neck squamous cell carcinoma ( HNSCC ) is primarily driven by tumor cell radioresistance leading to locoregional recurrence ( LRR ) .
22090360
PURPOSE : Mortality of patients with head and Cancerneck squamous cell carcinoma ( HNSCC ) is primarily driven by tumor cell radioresistance leading to locoregional recurrence ( LRR ) .
22090360
PURPOSE : Mortality of patients with head and neck squamous cell carcinoma ( HNSCC ) is primarily driven by Cancertumor cell radioresistance leading to locoregional recurrence ( LRR ) .
22090360
CONCLUSIONS : Disruptive TP53 mutations in CancerHNSCC tumors predicts for LRR , because of increased radioresistance via the inhibition of senescence .
22112610
PURPOSE : Efflux transporters of the ATP binding cassette ( ABC ) family are major determinants of chemoresistance in Cancertumor cells .
22112610
This study examined associations between functional variants in ABCB1 , ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian and Cancerprimary peritoneal cancer ( EOC and PPC ) following platinum and taxane based chemotherapy .
22112610
In multivariate analysis , patients with variant genotypes were at a AdverseOutcomereduced risk of disease progression ( hazard ratio [ HR ] = 0.75 , 95 % confidence interval [ CI ] = 0.59-0 .96 , p = 0.022 ) .
22112610
In multivariate analysis , patients with variant genotypes were at a reduced risk of Diseasedisease progression ( hazard ratio [ HR ] = 0.75 , 95 % confidence interval [ CI ] = 0.59-0 .96 , p = 0.022 ) .
22139083
Germline variants in the 3 ' untranslated region ( 3 ' UTR ) of Cancercancer genes disrupting microRNA ( miRNA ) regulation have recently been associated with cancer risk .
22139083
Germline variants in the 3 ' untranslated region ( 3 ' UTR ) of cancer genes disrupting microRNA ( miRNA ) regulation have recently been associated with Cancercancer risk .
22139083
Germline variants in the 3 ' untranslated region ( 3 ' UTR ) of cancer genes disrupting microRNA ( miRNA ) regulation have recently been associated with cancer AdverseOutcomerisk .
22139083
A variant in the 3 ' UTR of the KRAS oncogene , referred to as the KRAS variant , is associated with both Cancercancer risk and altered tumor biology .
22139083
A variant in the 3 ' UTR of the KRAS oncogene , referred to as the KRAS variant , is associated with both cancer AdverseOutcomerisk and altered tumor biology .
22139083
A variant in the 3 ' UTR of the KRAS oncogene , referred to as the KRAS variant , is associated with both cancer risk and Canceraltered tumor biology .
22139083
Here , we test the hypothesis that the KRAS variant can act as a biomarker of outcome in Cancerepithelial ovarian cancer ( EOC ) , and investigate the cause of altered outcome in KRAS variant positive EOC patients .
22139083
As this variant seems to be associated with Cancertumor biology , we additionally test the hypothesis that this variant can be directly targeted to impact cell survival .
22139083
Gene expression was analyzed on a subset of Cancertumors with available tissue .
22139083
Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of Cancerovarian cancer by multivariate analysis ( hazard ratio = 1.67 , 95 % confidence interval : 1.09-2 .57 , P = 0.019 , n = 279 ) .
22139083
These findings confirm the importance of the KRAS variant in EOC , and indicate that the KRAS variant is a biomarker of AdverseOutcomepoor outcome in EOC likely due to platinum resistance .
22139083
In addition , this study supports the hypothesis that these Cancertumors have continued dependence on such 3 ' UTR lesions , and that direct targeting may be a viable future treatment approach .
22149875
BACKGROUND : The anti-human epidermal growth factor receptor 2 ( HER2 ) humanized monoclonal antibody trastuzumab improves the outcome in patients with CancerHER2 positive metastatic breast cancer .
22149875
However , most cases of Diseaseadvanced disease eventually progress .
22149875
Pertuzumab , an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization , has a mechanism of action that is complementary to that of trastuzumab , and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with CancerHER2 positive breast cancer .
22149875
METHODS : We randomly assigned 808 patients with CancerHER2 positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed .
22149875
METHODS : We randomly assigned 808 patients with HER2 positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of Diseasedisease progression or the development of toxic effects that could not be effectively managed .
22149875
The safety profile was generally similar in the two groups , with no increase in left ventricular systolic dysfunction ; the rates of Diseasefebrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group .
22149875
CONCLUSIONS : The combination of pertuzumab plus trastuzumab plus docetaxel , as compared with placebo plus trastuzumab plus docetaxel , when used as first-line treatment for CancerHER2 positive metastatic breast cancer , significantly prolonged progression-free survival , with no increase in cardiac toxic effects .
22169769
To identify predictive biomarkers , sensitivity to GSK1120212 was profiled for 218 Cancersolid tumor cell lines and 81 hematologic malignancy cell lines .
22169769
To identify predictive biomarkers , sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 Cancerhematologic malignancy cell lines .
22169769
For Cancersolid tumors , RAF and RAS mutation was a strong predictor of sensitivity .
22169769
Among RAF and RAS mutant lines , co-occurring PIK3CA and PTEN mutations conferred a cytostatic response instead of a cytotoxic response for Cancercolon cancer cells that have the biggest representation of the comutations .
22169769
Among these were Cancerbreast cancer cell lines , with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes .
22169769
Among these were breast cancer cell lines , with Cancertriple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes .
22169769
Among these were breast cancer cell lines , with triple negative breast cancer cell lines being more sensitive than cell lines from Cancerother breast cancer subtypes .
22169769
Among hematologic cell lines , Canceracute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive .
22169769
Among hematologic cell lines , acute myeloid leukemia and Cancerchronic myeloid leukemia cell lines were particularly sensitive .
22169769
Overall , this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF and CancerRAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF and RAS wild-type status of their tumors .
22169769
Overall , this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF and RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF and RAS wild-type status of their Cancertumors .
22180162
DiseaseDISEASE OVERVIEW : Acute myeloid leukemia ( AML ) results from accumulation of abnormal immature cells in the marrow .
22180162
DISEASE OVERVIEW : CancerAcute myeloid leukemia ( AML ) results from accumulation of abnormal immature cells in the marrow .
22180162
It is likely that many different mutations and/or epigenetic aberrations can produce the Diseasesame disease , with these differences responsible for the very variable response to therapy , which is AML 's principal clinical feature .
22180162
AdverseOutcomeRISK STRATIFICATION : Two features determine risk : the probability of treatment related mortality ( TRM ) and , more important , even in patients aged > 75 with Zubrod performance status 1 , the probability of resistance to standard therapy despite not incurring TRM .
22180162
RISK STRATIFICATION : Two features determine AdverseOutcomerisk : the probability of treatment related mortality ( TRM ) and , more important , even in patients aged > 75 with Zubrod performance status 1 , the probability of resistance to standard therapy despite not incurring TRM .
22180162
RISK STRATIFICATION : Two features determine risk : the probability of treatment related AdverseOutcomemortality ( TRM ) and , more important , even in patients aged > 75 with Zubrod performance status 1 , the probability of resistance to standard therapy despite not incurring TRM .
22180162
The chief predictor of resistance is cytogenetics with a monosomal karyotype ( MK ) denoting the Diseasedisease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant ( HCT ) .
22180162
AdverseOutcomeRisk is best assessed considering several variables simultaneously rather than , for example , only age .
22180162
AdverseOutcomeRISK ADAPTED THERAPY : Patients with inv ( 16 ) or t ( 8 ; 21 ) or who are NPM1 +/FLT3ITD- can receive standard therapy ( daunorubicin + cytarabine ) and should not receive HCT in first CR .
22180178
BACKGROUND : There is a need for improved prognostic markers in Cancermelanoma .
22180178
In this study , the authors tested the prognostic significance and clinicopathologic correlations of Cancerv-raf murine sarcoma viral oncogene homolog B1 ( BRAF ) and neuroblastoma RAS viral ( v-ras ) oncogene homolog ( NRAS ) mutations in patients with metastatic melanoma .
22180178
In this study , the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ) and Cancerneuroblastoma RAS viral ( v-ras ) oncogene homolog ( NRAS ) mutations in patients with metastatic melanoma .
22180178
In this study , the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ) and neuroblastoma RAS viral ( v-ras ) oncogene homolog ( NRAS ) mutations in patients with Cancermetastatic melanoma .
22180178
METHODS : Clinical and pathologic data were collected retrospectively on Cancermelanoma patients who were clinically tested for BRAF ( exon 15 ) and NRAS ( exons 1 and 2 ) mutations at The University of Texas M. D. Anderson Cancer Center .
22180178
Analyses were performed to identify significant associations of mutations with Cancertumor and patient characteristics and with survival from the diagnosis of stage IV disease .
22180178
Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV Diseasedisease .
22180178
CancerTumor mutation status was associated ( P = .008 ) with the risk of central nervous system involvement at the diagnosis of stage IV disease , with a higher prevalence observed in BRAF-mutant ( 24 % ) and NRAS-mutant ( 23 % ) patients than in WT patients ( 12 % ) .
22180178
Tumor mutation status was associated ( P = .008 ) with the AdverseOutcomerisk of central nervous system involvement at the diagnosis of stage IV disease , with a higher prevalence observed in BRAF-mutant ( 24 % ) and NRAS-mutant ( 23 % ) patients than in WT patients ( 12 % ) .
22180178
Tumor mutation status was associated ( P = .008 ) with the risk of central nervous system involvement at the diagnosis of stage IV Diseasedisease , with a higher prevalence observed in BRAF-mutant ( 24 % ) and NRAS-mutant ( 23 % ) patients than in WT patients ( 12 % ) .
22180178
Among patients with Cancernonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis ( n = 313 ) , patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis , which was shorter than the median survival of WT patients ( 15.1 months ; P = .004 ) .
22180178
CONCLUSIONS : Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with Diseasedistant metastatic disease .
22180178
NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV Cancermelanoma .
22180495
Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8 % of all human ( solid ) Cancertumors , including 8 % to 10 % of colorectal cancers ( CRC ) .
22180495
Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8 % of all human ( solid ) tumors , including 8 % to 10 % of Cancercolorectal cancers ( CRC ) .
22180495
Here , we report the preclinical characterization of vemurafenib ( RG7204 ; PLX4032 ; RO5185426 ) , a first-in-class , specific small molecule inhibitor of BRAF ( V600E ) in BRAF mutated CRC cell lines and Cancertumor xenograft models .
22180495
As a single agent , vemurafenib shows dose dependent inhibition of ERK and MEK phosphorylation , thereby arresting cell proliferation in BRAF ( V600 )-expressing cell lines and inhibiting Cancertumor growth in BRAF ( V600E ) bearing xenograft models .
22180495
In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib ( RKO ) , Cancertumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor ( MK-2206 ) .
22190288
Therapeutic options for Cancermalignant pleural mesothelioma ( MPM ) are limited despite the increasing incidence globally .
22190288
BRCA1 regulates sensitivity to microtubule poisons ; however , its role in regulating vinorelbine induced apoptosis in Cancermesothelioma is unknown .
22190288
To determine whether loss of BRCA1 expression in Cancermesothelioma was potentially relevant in vivo , BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens .
22190288
To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo , BRCA1 immunohistochemistry was subsequently performed on 144 Cancerprimary mesothelioma specimens .
22190288
Together , these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in Cancermesothelioma , warranting its clinical evaluation as a predictive biomarker .
22194965
BACKGROUND : The sustained clinical activity of the BRAF inhibitor vemurafenib ( PLX4032 and RG7204 ) in patients with BRAF ( V600 ) Cancermutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression .
22194965
BACKGROUND : The sustained clinical activity of the BRAF inhibitor vemurafenib ( PLX4032 and RG7204 ) in patients with BRAF ( V600 ) mutant melanoma is limited primarily by the development of acquired resistance leading to Cancertumor progression .
22194965
Clinical trials are in progress using MEK inhibitors following Diseasedisease progression in patients receiving BRAF inhibitors .
22194965
METHODOLOGY and PRINCIPAL FINDINGS : The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and Cancerresistant human melanoma cell lines exploring differences in activation associated phosphorylation levels of major signaling molecules , leading to the testing of co-inhibition of the AKT and mTOR pathway genetically and pharmacologically .
22199315
Somatic mutations in the isocitrate dehydrogenase 1 ( IDH1 ) gene have been frequently found in Cancerlow-grade glioma and secondary glioblastoma and are associated with a significantly younger age at diagnosis and a superior overall survival .
22199315
Somatic mutations in the isocitrate dehydrogenase 1 ( IDH1 ) gene have been frequently found in low-grade glioma and Cancersecondary glioblastoma and are associated with a significantly younger age at diagnosis and a superior overall survival .
22199315
We investigated the IDH1 gene mutation status by nested PCR and denaturing gradient gel electrophoresis ( DGGE ) on DNA extracted from Cancerarchival tumor blocks of 63 glioma patients who were treated following recurrence with the epidermal growth factor receptor ( EGFR )-targeted blocking monoclonal antibody cetuximab , or the vascular endothelial growth factor ( receptor ) ( VEGF ( R ) )-targeted agents sunitinib malate and bevacizumab .
22199315
We investigated the IDH1 gene mutation status by nested PCR and denaturing gradient gel electrophoresis ( DGGE ) on DNA extracted from archival tumor blocks of 63 Cancerglioma patients who were treated following recurrence with the epidermal growth factor receptor ( EGFR )-targeted blocking monoclonal antibody cetuximab , or the vascular endothelial growth factor ( receptor ) ( VEGF ( R ) )-targeted agents sunitinib malate and bevacizumab .
22199315
Our observations support the hypothesis that IDH1 mutation may correlate with the benefit from VEGF ( R ) - versus EGFR targeted therapy at the time of recurrence in Cancerglioma patients .
22203985
Because oncogene MET and EGF receptor ( EGFR ) inhibitors are in clinical development against several types of Cancercancer , including glioblastoma , it is important to identify predictive markers that indicate patient subgroups suitable for such therapies .
22203985
Because oncogene MET and EGF receptor ( EGFR ) inhibitors are in clinical development against several types of cancer , including Cancerglioblastoma , it is important to identify predictive markers that indicate patient subgroups suitable for such therapies .
22203985
We investigated in vivo Cancerglioblastoma models characterized by hepatocyte growth factor ( HGF ) autocrine or paracrine activation , or by MET or EGFR amplification , for their susceptibility to MET inhibitors .
22203985
An HGF paracrine environment may enhance Cancerglioblastoma growth in vivo but did not indicate sensitivity to MET inhibition .
22203985
EGFRvIII amplification predicted sensitivity to EGFR inhibition , but in the Cancersame tumor , increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors .
22203985
Thus , CancerHGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors .
22203985
Moreover , serum HGF levels may serve as a biomarker for the presence of Cancerautocrine tumors and their responsiveness to MET therapeutics .
22210878
CancerMantle cell lymphoma ( MCL ) , an aggressive subtype of non Hodgkin lymphoma , is characterized by the hallmark translocation t ( 11 ; 14 ) ( q13 ; q32 ) and the resulting overexpression of cyclin D1 ( CCND1 ) .
22210878
Mantle cell lymphoma ( MCL ) , an aggressive subtype of Cancernon Hodgkin lymphoma , is characterized by the hallmark translocation t ( 11 ; 14 ) ( q13 ; q32 ) and the resulting overexpression of cyclin D1 ( CCND1 ) .
22210878
Our current knowledge of this Diseasedisease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes , such as TP53 , ATM , and CCND1 .
22215748
PURPOSE : Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of Cancernon-small-cell lung cancers ( NSCLCs ) .
22215748
Because little is known about these Cancertumors , we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement .
22215748
RESULTS : Of 1,073 Cancertumors screened , 18 ( 1.7 % ) were ROS1 rearranged by FISH , and 31 ( 2.9 % ) were ALK rearranged .
22215748
All of the CancerROS1 positive tumors were adenocarcinomas , with a tendency toward higher grade .
22215748
All of the ROS1 positive tumors were Canceradenocarcinomas , with a tendency toward higher grade .
22215748
The patient treated with crizotinib showed Cancertumor shrinkage , with a near complete response .
22215888
Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and isocitrate dehydrogenase 2 ( IDH2 ) occur in most grade 2 and 3 Cancergliomas , secondary glioblastomas , and a subset of acute myelogenous leukemias but have not been detected in other tumor types .
22215888
Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and isocitrate dehydrogenase 2 ( IDH2 ) occur in most grade 2 and 3 gliomas , Cancersecondary glioblastomas , and a subset of acute myelogenous leukemias but have not been detected in other tumor types .
22215888
Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and isocitrate dehydrogenase 2 ( IDH2 ) occur in most grade 2 and 3 gliomas , secondary glioblastomas , and a subset of Canceracute myelogenous leukemias but have not been detected in other tumor types .
22215888
Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and isocitrate dehydrogenase 2 ( IDH2 ) occur in most grade 2 and 3 gliomas , secondary glioblastomas , and a subset of acute myelogenous leukemias but have not been detected in Cancerother tumor types .
22215888
This study reports IDH1 and IDH2 genotyping results from a set of Cancerlymphomas , which included a large set of peripheral T-cell lymphomas .
22215888
This study reports IDH1 and IDH2 genotyping results from a set of lymphomas , which included a large set of Cancerperipheral T-cell lymphomas .
22215888
IDH2 mutations were identified in approximately 20 % of Cancerangioimmunoblastic T-cell lymphomas ( AITLs ) , but not in other peripheral T-cell lymphoma entities .
22215888
IDH2 mutations were identified in approximately 20 % of angioimmunoblastic T-cell lymphomas ( AITLs ) , but not in Cancerother peripheral T-cell lymphoma entities .
22215888
This is the second common genetic lesion identified in AITL after TET2 and extends the number of Diseaseneoplastic diseases where IDH1 and IDH2 mutations may play a role .
22235099
PURPOSE : Patients with Canceranaplastic lymphoma kinase ( ALK ) gene rearrangements often manifest dramatic responses to crizotinib , a small-molecule ALK inhibitor .
22235099
This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK ( + ) Cancernon small cell lung cancer ( NSCLC ) .
22235099
One patient showed the emergence of an CancerALK gene fusion negative tumor compared with the baseline sample but with no identifiable alternate driver .
22238366
Members of the fibroblast growth factor receptor family of kinases ( FGFR1-4 ) are dysregulated in Cancermultiple cancers .
22238366
Ponatinib ( AP24534 ) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with Cancerchronic myelogenous leukemia due to its potent activity against BCR-ABL .
22238366
In a panel of 14 cell lines representing Cancermultiple tumor types ( endometrial , bladder , gastric , breast , lung , and colon ) and containing FGFRs dysregulated by a variety of mechanisms , ponatinib inhibited FGFR mediated signaling with IC ( 50 ) values < 40 nmol/L and inhibited cell growth with GI ( 50 ) ( concentration needed to reduce the growth of treated cells to half that of untreated cells ) values of 7 to 181 nmol/L .
22238366
Daily oral dosing of ponatinib ( 10-30 mg/kg ) to mice reduced Cancertumor growth and inhibited signaling in all three tumor models examined .
22238366
Daily oral dosing of ponatinib ( 10-30 mg/kg ) to mice reduced tumor growth and inhibited signaling in all three Cancertumor models examined .
22238366
These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR driven Cancercancers .
22247021
BACKGROUND : Mutations in the Cancerv-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) play a critical role in cancer cell growth and resistance to therapy .
22247021
BACKGROUND : Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) play a critical role in Cancercancer cell growth and resistance to therapy .
22247021
In Cancercolorectal cancer , the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy .
22247021
However , in Cancernon small cell lung cancer ( NSCLC ) , the evidence that KRAS mutation is a predictive factor is conflicting .
22247021
METHODS : We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and Cancertumor gene expression .
22247021
Transcriptome microarray studies of Cancerpatient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation .
22247021
RESULTS : Patients whose Cancertumors had either mutant KRas Gly12Cys or mutant KRas Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas ( P = .046 , median survival = 1.84 months ) compared with all other mutant KRas ( median survival = 3.35 months ) or wild-type KRas ( median survival = 1.95 months ) .
22247021
RESULTS : Patients whose tumors had either mutant KRas Gly12Cys or mutant KRas Gly12Val had worse progression-free survival compared with patients whose Cancertumors had other mutant KRas proteins or wild-type KRas ( P = .046 , median survival = 1.84 months ) compared with all other mutant KRas ( median survival = 3.35 months ) or wild-type KRas ( median survival = 1.95 months ) .
22247021
The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the Cancertumor .
22252991
BACKGROUND : Several promising molecular targeted drugs are used for Canceradvanced renal cancers .
22252991
However , complete remission is rarely achieved , because none of the drugs targets a key molecule that is specific to the Cancercancer , or is associated with " oncogene addiction " ( dependence on one or a few oncogenes for cell survival ) of renal cancer .
22252991
However , complete remission is rarely achieved , because none of the drugs targets a key molecule that is specific to the cancer , or is associated with " oncogene addiction " ( dependence on one or a few oncogenes for cell survival ) of Cancerrenal cancer .
22252991
Recently , an Canceranaplastic lymphoma kinase ( ALK ) fusion , vinculin-ALK , has been reported in pediatric renal cell carcinoma ( RCC ) cases who have a history of sickle cell trait .
22252991
Recently , an anaplastic lymphoma kinase ( ALK ) fusion , vinculin-ALK , has been reported in Cancerpediatric renal cell carcinoma ( RCC ) cases who have a history of sickle cell trait .
22252991
In this context , ALK inhibitor therapy would constitute a therapeutic advance , as has previously been demonstrated with Cancerlung cancer , inflammatory myofibroblastic tumors , and anaplastic large cell lymphomas .
22252991
In this context , ALK inhibitor therapy would constitute a therapeutic advance , as has previously been demonstrated with lung cancer , Cancerinflammatory myofibroblastic tumors , and anaplastic large cell lymphomas .
22252991
In this context , ALK inhibitor therapy would constitute a therapeutic advance , as has previously been demonstrated with lung cancer , inflammatory myofibroblastic tumors , and Canceranaplastic large cell lymphomas .
22252991
METHODS : Anti-ALK immunohistochemistry was used to screen 355 Cancertumor tissues , using the intercalated antibody enhanced polymer ( iAEP ) method .
22252991
The cohort consisted of 255 clear cell RCCs , 32 papillary RCCs , 34 chromophobe RCCs , 6 collecting Cancerduct carcinomas , 10 unclassified RCCs , 6 sarcomatoid RCCs , and 12 other tumors .
22252991
The cohort consisted of 255 clear cell RCCs , 32 papillary RCCs , 34 chromophobe RCCs , 6 collecting duct carcinomas , 10 unclassified RCCs , 6 sarcomatoid RCCs , and 12 Cancerother tumors .
22252991
Using 5 '- rapid amplification of complementary DNA ends , we detected TPM3-ALK and EML4-ALK in these Cancertumors .
22257673
BACKGROUND : The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2 overexpressing Cancerbreast cancer .
22257673
METHODS : In this parallel groups , randomised , open-label , phase 3 study undertaken between Jan 5 , 2008 , and May 27 , 2010 , women from 23 countries with CancerHER2 positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib ( 1500 mg ) , intravenous trastuzumab ( loading dose 4 mg/kg [ DOSAGE ERROR CORRECTED ] , subsequent doses 2 mg/kg ) , or lapatinib ( 1000 mg ) plus trastuzumab .
22257673
METHODS : In this parallel groups , randomised , open-label , phase 3 study undertaken between Jan 5 , 2008 , and May 27 , 2010 , women from 23 countries with HER2 positive primary breast cancer with Cancertumours greater than 2 cm in diameter were randomly assigned to oral lapatinib ( 1500 mg ) , intravenous trastuzumab ( loading dose 4 mg/kg [ DOSAGE ERROR CORRECTED ] , subsequent doses 2 mg/kg ) , or lapatinib ( 1000 mg ) plus trastuzumab .
22257673
INTERPRETATION : Dual inhibition of HER2 might be a valid approach to treatment of CancerHER2 positive breast cancer in the neoadjuvant setting .
22261812
PURPOSE : Recent studies have shown activating KIT mutations in Cancermelanoma originating from mucosa , acral , or cumulative sun damaged skin sites .
22261812
EXPERIMENTAL DESIGN : CancerTumor tissues from 90 patients with stage III or IV acral , mucosal , or cumulative sun damaged skin melanoma underwent sequencing of KIT , BRAF , NRAS , and GNAQ genes , FISH analysis for KIT amplification , and immunohistochemistry of KIT protein ( CD117 ) .
22261812
EXPERIMENTAL DESIGN : Tumor tissues from 90 patients with stage III or IV acral , mucosal , or cumulative sun damaged Cancerskin melanoma underwent sequencing of KIT , BRAF , NRAS , and GNAQ genes , FISH analysis for KIT amplification , and immunohistochemistry of KIT protein ( CD117 ) .
22261812
Patients with mutations , amplifications , or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in CancerSolid Tumors ( RECIST ) .
22261812
RESULTS : Eleven percent of the Cancermelanomas tested had mutations in KIT , 23 % in BRAF , 14 % in NRAS , and none in GNAQ .
22261812
In 1 responder with Cancerrectal melanoma who later progressed , the recurring tumor had a previously undetected mutation in NRAS , which was found in addition to the persisting mutation in KIT .
22261812
In 1 responder with rectal melanoma who later progressed , the recurring Cancertumor had a previously undetected mutation in NRAS , which was found in addition to the persisting mutation in KIT .
22261812
Interestingly , among patients with manifest stage IV Diseasedisease , KIT mutations were associated with a significantly shortened survival time ( P < 0.0001 ) .
22261812
CONCLUSIONS : Sunitinib may have activity in patients with Cancermelanoma and KIT mutations ; more study is needed .
22261812
KIT mutations may represent an adverse prognostic factor in Cancermetastatic melanoma .
22262166
ATP-competitive mTOR kinase inhibitors ( mTorKIs ) are a new generation of mTOR targeted agents with more potent anticancer activity than rapamycin in Cancerseveral tumor models .
22262166
However , the sensitivity and resistance of Cancercancer cells to mTorKIs remain poorly understood .
22262166
In this study , we tested mTorKIs against a large panel of Cancercolorectal cancer ( CRC ) cell lines , and found that mTorKIs displayed broader anti-CRC activity than rapamycin , including CRC cells with K-Ras or B-Raf mutations , suggesting that these mTorKIs are particularly useful for CRCs resistant to EGFR inhibitors .
22262166
They further reveal the existence of significant intrinsic mTorKI drug resistance in Cancercancer cells and suggest that 4E-BP1 phosphorylation is a predictive biomarker for mTorKI sensitivity and resistance .
22270724
Antibodies against epidermal growth factor receptor ( EGFR ) -- cetuximab and panitumumab -- are widely used to treat Cancercolorectal cancer .
22270724
Two of ten subjects studied here with Diseasedisease progression after cetuximab treatment acquired this mutation .
22274685
CONTEXT : Approximately 10 % of women with Cancerinvasive epithelial ovarian cancer ( EOC ) carry deleterious germline mutations in BRCA1 or BRCA2 .
22274685
DESIGN , SETTING , AND PARTICIPANTS : A pooled analysis of 26 observational studies on the survival of women with Cancerovarian cancer , which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 ( n = 909 ) or BRCA2 ( n = 304 ) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 ( the median year of diagnosis was 1998 ) .
22274685
MAIN OUTCOME MEASURE : Five-year overall AdverseOutcomemortality .
22277784
CancerMost anaplastic lymphoma kinase ( ALK )-positive non small cell lung cancers ( NSCLCs ) are highly responsive to treatment with ALK tyrosine kinase inhibitors ( TKIs ) .
22277784
Most anaplastic lymphoma kinase ( CancerALK )-positive non small cell lung cancers ( NSCLCs ) are highly responsive to treatment with ALK tyrosine kinase inhibitors ( TKIs ) .
22277784
However , patients with these Cancercancers invariably relapse , typically within 1 year , because of the development of drug resistance .
22277784
Herein , we report findings from a series of Cancerlung cancer patients ( n = 18 ) with acquired resistance to the ALK TKI crizotinib .
22277784
In addition to secondary ALK mutations and ALK gene amplification , we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in Cancerdrug resistant tumors from patients .
22281684
Inhibition of the BRAF ( V600E ) oncoprotein by the small-molecule drug PLX4032 ( vemurafenib ) is highly effective in the treatment of Cancermelanoma .
22281684
However , Cancercolon cancer patients harbouring the same BRAF ( V600E ) oncogenic lesion have poor prognosis and show only a very limited response to this drug .
22281684
However , colon cancer patients harbouring the same BRAF ( V600E ) oncogenic lesion have AdverseOutcomepoor prognosis and show only a very limited response to this drug .
22281684
To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF ( V600E ) Cancermutant colon tumours , here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF ( V600E ) inhibition .
22281684
We find in multiple BRAF ( V600E ) Cancermutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF ( V600E ) inhibition , both in vitro and in vivo .
22281684
CancerMelanoma cells express low levels of EGFR and are therefore not subject to this feedback activation .
22281684
Consistent with this , we find that ectopic expression of EGFR in Cancermelanoma cells is sufficient to cause resistance to PLX4032 .
22281684
Our data suggest that BRAF ( V600E ) Cancermutant colon cancers ( approximately 8-10 % of all colon cancers ) , for which there are currently no targeted treatment options available , might benefit from combination therapy consisting of BRAF and EGFR inhibitors .
22281684
Our data suggest that BRAF ( V600E ) mutant colon cancers ( approximately 8-10 % of all Cancercolon cancers ) , for which there are currently no targeted treatment options available , might benefit from combination therapy consisting of BRAF and EGFR inhibitors .
22285168
BACKGROUND : Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with Cancernon-small-cell lung cancer ( NSCLC ) with activating EGFR mutations .
22285168
Eligible participants were adults ( > 18 years ) with NSCLC and EGFR mutations ( exon 19 deletion or L858R mutation in exon 21 ) with no history of chemotherapy for Diseasemetastatic disease ( neoadjuvant or adjuvant chemotherapy ending > = 6 months before study entry was allowed ) .
22285168
Main grade 3 or 4 Diseasetoxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) .
22285168
Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , Diseaseneutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) .
22285168
Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , Diseaseanaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) .
22291079
PURPOSE : To determine the frequency of DNMT3A mutations , their associations with clinical and molecular characteristics and outcome , and the associated gene- and microRNA expression signatures in primary cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) .
22292935
BACKGROUND : The phosphoinositide 3-kinase ( PI3K )/Akt pathway plays a fundamental role in cell proliferation and survival in human tumorigenesis , including Cancergastric cancer .
22292935
PIK3CA mutations and amplification are two major causes of overactivation of this pathway in Cancerhuman cancers .
22292935
However , until this work , there was no sound investigation on the association of PIK3CA mutations and amplification with clinical outcome in Cancergastric cancer , particularly the latter .
22292935
METHODS : Using direct sequencing and real-time quantitative PCR , we examined PIK3CA mutations and amplification , and their association with clinicopathological characteristics and clinical outcome of Cancergastric cancer patients .
22292935
RESULTS : PIK3CA mutations and amplification were found in 8/113 ( 7.1 % ) and 88/131 ( 67 % ) Cancergastric cancer patients , respectively .
22292935
No relationship was found between PIK3CA mutations and clinicopathological characteristics and clinical outcome in Cancergastric cancer .
22292935
PIK3CA amplification was significantly positively associated with Cancercancer related death .
22292935
CONCLUSIONS : Our data showed that PIK3CA mutations were not common , but its amplification was very common in Cancergastric cancer and may be a major mechanism in activating the PI3K and Akt pathway in gastric cancer .
22292935
CONCLUSIONS : Our data showed that PIK3CA mutations were not common , but its amplification was very common in gastric cancer and may be a major mechanism in activating the PI3K and Akt pathway in Cancergastric cancer .
22292935
Importantly , Kaplan-Meier survival curves revealed that PIK3CA amplification was significantly positively associated with poor survival of Cancergastric cancer patients .
22292935
Collectively , the PI3K and Akt signaling pathway may be an effective therapeutic target in Cancergastric cancer .
22294718
AKT is a key node in the most frequently deregulated signaling network in Cancerhuman cancer .
22294718
AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and Cancerhematologic tumor cell lines with a potency of 3 mumol/L or less .
22294718
Cell lines derived from Cancerbreast cancers showed the highest frequency of sensitivity .
22294718
Chronic oral dosing of AZD5363 caused dose dependent growth inhibition of xenografts derived from Cancervarious tumor types , including HER2 ( + ) breast cancer models that are resistant to trastuzumab .
22294718
Chronic oral dosing of AZD5363 caused dose dependent growth inhibition of xenografts derived from various tumor types , including HER2 ( + ) Cancerbreast cancer models that are resistant to trastuzumab .
22294718
AZD5363 also significantly enhanced the antitumor activity of docetaxel , lapatinib , and trastuzumab in Cancerbreast cancer xenografts .
22294718
It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo , has potential to treat a range of solid and Cancerhematologic tumors as monotherapy or a combinatorial agent , and has potential for personalized medicine based on the genetic status of PIK3CA , PTEN , and RAS .
22296372
OBJECTIVE : To evaluate the influence of multi-drug resistance 1 ( MDR1 ) gene codon 3435 polymorphisms on response to platinum based chemotherapeutic regimens for Canceradvanced non small cell lung cancer ( NSCLC ) .
22302096
CancerEsophageal adenocarcinomas are poorly responsive to chemotherapeutics .
22302096
Using quantitative real-time PCR , we detected frequent AURKA gene amplification ( 15 of 34 , 44 % ) and mRNA overexpression ( 37 of 44 , 84 % ) in Canceresophageal adenocarcinomas ( P < 0.01 ) .
22302096
Immunohistochemical analysis showed overexpression of AURKA in more than two-thirds of Canceresophageal adenocarcinoma tissue samples ( 92 of 132 , 70 % ; P < 0.001 ) .
22302096
Using FLO-1 , OE19 , and CancerOE33 esophageal adenocarinoma cell lines , with constitutive AURKA overexpression and mutant p53 , we observed inhibition of colony formation with a single treatment of 0.5 mumol/L MLN8237 ( P < 0.05 ) .
22302096
In conclusion , this study shows frequent overexpression of AURKA and suggests that MLN8237 could be an effective antitumor agent , which can be combined with cisplatin for a better therapeutic outcome in Canceresophageal adenocarcinomas .
22325357
Human epidermal growth factor receptor ( HER ) 2/neu kinase domain mutations are found in approximately 1-4 % of Cancerlung adenocarcinomas with a similar phenotype to tumors with epidermal growth factor receptor ( EGFR ) mutations .
22325357
Human epidermal growth factor receptor ( HER ) 2/neu kinase domain mutations are found in approximately 1-4 % of lung adenocarcinomas with a similar phenotype to Cancertumors with epidermal growth factor receptor ( EGFR ) mutations .
22325357
We determined the Cancertumor genomic status of the EGFR and HER2 genes in non- or light smokers with lung adenocarcinoma in patients who were entered into an exploratory Phase II study with afatinib .
22325357
We determined the tumor genomic status of the EGFR and HER2 genes in non- or light smokers with Cancerlung adenocarcinoma in patients who were entered into an exploratory Phase II study with afatinib .
22325357
Five patients with a non smoking history and Cancermetastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified , three of which were evaluable for response .
22328973
While genomically targeted therapies have improved outcomes for patients with Cancerlung adenocarcinoma , little is known about the genomic alterations which drive squamous cell lung cancer .
22328973
While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma , little is known about the genomic alterations which drive Cancersquamous cell lung cancer .
22328973
Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8 % of Cancersquamous cell lung cancers and cell lines .
22328973
CancerSquamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi targeted kinase inhibitor dasatinib .
22328973
CancerTumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models .
22328973
A Cancersquamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation .
22333600
METHODS : We analysed the anti-tumour effects of enzastaurin in 22 Cancerlung cancer cell lines to ascertain the potential for enzastaurin based treatment of lung cancer .
22333600
METHODS : We analysed the anti-tumour effects of enzastaurin in 22 lung cancer cell lines to ascertain the potential for enzastaurin based treatment of Cancerlung cancer .
22333600
The anti-tumour effect of enzastaurin should be evaluated in Cancerlung cancer with overexpressed JAK pathway molecules .
22343617
BACKGROUND : To evaluate the activity and safety of everolimus and identify potential biomarkers for efficacy of everolimus in patients with Canceradvanced gastric cancer ( AGC ) , who failed both fluoropyrimidine and platinum .
22343617
We additionally investigated the potential biomarkers for everolimus as an exploratory endpoint in those who underwent Cancertumour biopsies .
22343617
RESULTS : Two patients ( 3.7 % ) achieved partial response and the Diseasedisease control rate ( DCR ) was 38.9 % .
22343617
Grade 1/2 Diseaseasthenia ( 96.3 % ) recorded as the leading toxicity and hyperglycaemia ( 20.4 % ) was the most common non hematological grade 3/4 toxicity .
22343617
Grade 1/2 asthenia ( 96.3 % ) recorded as the leading Diseasetoxicity and hyperglycaemia ( 20.4 % ) was the most common non hematological grade 3/4 toxicity .
22343617
Grade 1/2 asthenia ( 96.3 % ) recorded as the leading toxicity and Diseasehyperglycaemia ( 20.4 % ) was the most common non hematological grade 3/4 toxicity .
22343617
Grade 1/2 asthenia ( 96.3 % ) recorded as the leading toxicity and hyperglycaemia ( 20.4 % ) was the most common non hematological grade 3/4 Diseasetoxicity .
22343617
Three patients experienced grade 3/4 Diseasepneumonitis .
22343617
Careful monitoring is necessary despite generally Diseasefavourable toxicity profile .
22356324
BACKGROUND : Approximately 50 % of Cancermelanomas harbor activating ( V600 ) mutations in the serine threonine protein kinase B-RAF ( BRAF ) .
22356324
The oral BRAF inhibitor vemurafenib ( PLX4032 ) frequently produced Cancertumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial .
22356324
The oral BRAF inhibitor vemurafenib ( PLX4032 ) frequently produced tumor regressions in patients with CancerBRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial .
22356324
METHODS : We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated CancerBRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate ( percentage of treated patients with a tumor response ) , duration of response , and overall survival .
22356324
METHODS : We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate ( percentage of treated patients with a Cancertumor response ) , duration of response , and overall survival .
22356324
CancerCutaneous squamous-cell carcinomas ( the majority , keratoacanthoma type ) were diagnosed in 26 % of patients .
22356324
Cutaneous squamous-cell carcinomas ( the majority , Cancerkeratoacanthoma type ) were diagnosed in 26 % of patients .
22356324
CONCLUSIONS : Vemurafenib induces clinical responses in more than half of patients with previously treated CancerBRAF V600-mutant metastatic melanoma .
22357840
Thus , we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in Cancercolorectal cancer , and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior .
22357840
Thus , we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer , and that concomitant PIK3CA exon 9 and 20 mutations might confer Canceraggressive tumor behavior .
22357840
EXPERIMENTAL DESIGN : We sequenced PIK3CA by pyrosequencing in 1,170 rectal and Cancercolon cancers in two prospective cohort studies , and found 189 ( 16 % ) PIK3CA mutated tumors .
22357840
EXPERIMENTAL DESIGN : We sequenced PIK3CA by pyrosequencing in 1,170 rectal and colon cancers in two prospective cohort studies , and found 189 ( 16 % ) PIK3CA mutated Cancertumors .
22357840
AdverseOutcomeMortality HR according to PIK3CA status was computed using Cox proportional hazards model , adjusting for clinical and molecular features , including microsatellite instability , CpG island methylator phenotype , LINE-1 methylation , and BRAF and KRAS mutations .
22357840
RESULTS : Compared with PIK3CA wild-type cases , patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly Cancerworse cancer specific survival [ log-rank P = 0.031 ; multivariate HR = 3.51 ; 95 % confidence interval ( CI ) : 1.28-9 .62 ] and overall survival ( log-rank P = 0.0008 ; multivariate HR = 2.68 ; 95 % CI : 1.24-5 .77 ) .
22357840
CONCLUSION : Coexistence of PIK3CA ( the PI3K p110alpha subunit ) exon 9 and 20 mutations , but not PIK3CA mutation in either exon 9 or 20 alone , is associated with AdverseOutcomepoor prognosis of colorectal cancer patients .
22357840
CONCLUSION : Coexistence of PIK3CA ( the PI3K p110alpha subunit ) exon 9 and 20 mutations , but not PIK3CA mutation in either exon 9 or 20 alone , is associated with poor prognosis of Cancercolorectal cancer patients .
22368270
Internal tandem duplication ( ITD ) of the fms related tyrosine kinase-3 ( FLT3 ) gene occurs in 30 % of Canceracute myeloid leukemias ( AMLs ) and confers a poor prognosis .
22368270
Internal tandem duplication ( ITD ) of the fms related tyrosine kinase-3 ( FLT3 ) gene occurs in 30 % of acute myeloid leukemias ( AMLs ) and confers a AdverseOutcomepoor prognosis .
22368270
Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 ( range 21-84 ) days with evidence of differentiation of Cancerleukemia cells .
22368270
Gene expression profiling showed that Cancerleukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1 , JAK3 , and MMP15 , whose functions were unknown in AML .
22368270
Nonobese diabetic and severe combined immunodeficiency mice transplanted with Cancerleukemia cells from patients before and during sorafenib resistance recapitulated the clinical results .
22368270
Both ITD and tyrosine kinase domain mutations at D835 were identified in Cancerleukemia initiating cells ( LICs ) from samples before sorafenib treatment .
22370314
PURPOSE : Gefitinib has shown high response rate and improved progression-free survival ( PFS ) in never-smokers with Cancerlung adenocarcinoma ( NSLAs ) .
22370314
PATIENTS AND METHODS : In this randomized phase III trial , a total of 313 Korean never-smokers with stage IIIB or IV Cancerlung adenocarcinoma , Eastern Cooperative Oncology Group performance status 0 to 2 , and adequate organ function were randomly assigned to receive either gefitinib ( 250 mg daily ) or GP chemotherapy ( gemcitabine 1,250 mg/m ( 2 ) on days 1 and 8 ; cisplatin 80 mg/m ( 2 ) on day 1 every 3 weeks , for up to nine courses ) .
22370314
Myelosuppression , renal insufficiency , and fatigue were more common in the GP arm , but Diseaseskin toxicities and liver dysfunction were more common in the gefitinib arm .
22370314
Two patients ( 1.3 % ) in the gefitinib arm developed Diseaseinterstitial lung disease and died .
22383795
CancerMantle cell lymphoma ( MCL ) carries an unfavorable prognosis and requires new treatment strategies .
22383795
A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed Diseasedisease , using 2-deoxy-2-[ ( 18 ) F ] fluoro-D-glucose ( FDG ) and 3-deoxy-3 [ ( 18 ) F ] fluorothymidine ( FLT ) positron emission tomography ( PET ) to study tumor metabolism and proliferation , respectively , in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein ( Rb ) phosphorylation and markers of proliferation and apoptosis .
22383795
A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease , using 2-deoxy-2-[ ( 18 ) F ] fluoro-D-glucose ( FDG ) and 3-deoxy-3 [ ( 18 ) F ] fluorothymidine ( FLT ) positron emission tomography ( PET ) to study Cancertumor metabolism and proliferation , respectively , in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein ( Rb ) phosphorylation and markers of proliferation and apoptosis .
22383795
A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease , using 2-deoxy-2-[ ( 18 ) F ] fluoro-D-glucose ( FDG ) and 3-deoxy-3 [ ( 18 ) F ] fluorothymidine ( FLT ) positron emission tomography ( PET ) to study tumor metabolism and proliferation , respectively , in concert with pre- and on-treatment lymph node biopsies to assess Cancerretinoblastoma protein ( Rb ) phosphorylation and markers of proliferation and apoptosis .
22383795
These patients demonstrated > 70 % , > 90 % , and > = 87.5 % reductions in summed FLT SUV ( max ) and expression of phospho-Rb and Ki67 , respectively , parameters necessary but not sufficient for Diseaselong-term disease control .
22389872
A 48 year-old female with Cancerchemo-refractory metastatic gastric cancer to the liver was treated on a Phase I clinical trial with MetMAb , a monoclonal antibody targeting the Met tyrosine kinase receptor .
22389872
The Cancerprimary tumor had high MET gene polysomy and evidence for an autocrine production of HGF , the growth factor ligand of Met .
22389872
A complete response was obtained lasting two years ; the Cancercancer recurred as a peritoneal deposit invading into the transverse colon and a gastrohepatic ligament node .
22389872
Tissue and serum studies evaluating the Met signaling pathway did correlate with MetMAb treatment response initially and at the time of recurrence.SIGNIFICANCE : This research brief is the first to describe a durable complete response obtained with a molecularly targeted monoclonal antibody , MetMAb , to the receptor tyrosine kinase , Met , in a patient with Cancerchemorefractory metastatic gastric cancer .
22417203
BACKGROUND : CancerAcute myeloid leukemia ( AML ) is a heterogeneous disease with respect to presentation and clinical outcome .
22417203
BACKGROUND : Acute myeloid leukemia ( AML ) is a Diseaseheterogeneous disease with respect to presentation and clinical outcome .
22417203
We identified genetic predictors of outcome that improved AdverseOutcomerisk stratification among patients with AML , independently of age , white-cell count , induction dose , and post-remission therapy , and validated the significance of these predictors in an independent cohort .
22417203
These findings suggest that mutational profiling could potentially be used for AdverseOutcomerisk stratification and to inform prognostic and therapeutic decisions regarding patients with AML .
22418700
This phase II , open-label , single-arm study explored afatinib activity in human epidermal growth factor receptor 2 ( CancerHER2 )-positive breast cancer patients progressing after trastuzumab treatment .
22418700
Patients had Cancerstage IIIB/IV HER2 positive metastatic breast cancer , with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0-2 .
22418700
Patients received 50 mg afatinib once-daily until Diseasedisease progression .
22418700
Primary endpoint was objective response rate ( Response Evaluation Criteria in CancerSolid Tumors 1.0 ) , with tumor assessments every 8 weeks .
22418700
Primary endpoint was objective response rate ( Response Evaluation Criteria in Solid Tumors 1.0 ) , with Cancertumor assessments every 8 weeks .
22418700
Fifteen patients ( 37 % of 41 ) had Diseasestable disease as best response and 19 ( 46 % of 41 ) achieved clinical benefit .
22418700
Afatinib monotherapy was associated with promising clinical activity in extensively Cancerpretreated HER2 positive breast cancer patients who had progressed following trastuzumab treatment .
22422354
Raltitrexed is a novel water-soluble quinazoline folate analogue and can improve the efficiency of Cancergastric cancer treatment , but its predictive biomarker remains unclear .
22422354
The aim of our study was to investigate the role of plasma and Cancertumor thymidylate synthase ( TS ) mRNA levels as predictive biomarkers for raltitrexed in gastric cancer .
22422354
The aim of our study was to investigate the role of plasma and tumor thymidylate synthase ( TS ) mRNA levels as predictive biomarkers for raltitrexed in Cancergastric cancer .
22422354
In total , 125 freshly removed Cancergastric tumor specimens and corresponding blood samples before surgery were collected .
22422354
TS mRNA levels in Cancertumor and plasma were determined by quantitative reverse transcription polymerase chain reaction .
22422354
Plasma TS mRNA level in Cancercancer patients was significantly higher than in healthy subjects ( p = 0.009 ) and was significantly correlated with TS mRNA level in tumor tissues ( r = 0.665 , p < 0.001 ) .
22422354
Plasma TS mRNA level in cancer patients was significantly higher than in healthy subjects ( p = 0.009 ) and was significantly correlated with TS mRNA level in Cancertumor tissues ( r = 0.665 , p < 0.001 ) .
22422354
CancerTumor and plasma TS mRNA expression levels were significantly lower in raltitrexed sensitive group than in resistant group ( p = 0.007 and 0.013 , respectively ) .
22422354
The sensitivity and accuracy of raltitrexed sensitivity prediction based on plasma TS mRNA levels were 82 and 60 % , respectively , whereas the prediction based on Cancertumor TS mRNA reached 70 % sensitivity and 68 % accuracy .
22422354
These results indicate that TS mRNA level in plasma can mirror Cancertumor TS mRNA level , and both of them can be used to predict raltitrexed sensitivity in gastric cancer .
22422354
These results indicate that TS mRNA level in plasma can mirror tumor TS mRNA level , and both of them can be used to predict raltitrexed sensitivity in Cancergastric cancer .
22425996
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined Cancercancers .
22425996
Although most patients with Cancerlung cancer are stratified according to a single oncogenic driver , cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy .
22425996
Although most patients with lung cancer are stratified according to a single oncogenic driver , Cancercancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy .
22425996
Here we use genetically engineered mouse models to conduct a ' co-clinical ' trial that mirrors an ongoing human clinical trial in patients with CancerKRAS-mutant lung cancers .
22425996
Our studies demonstrate that concomitant loss of either p53 ( also known as Tp53 ) or Lkb1 ( also known as Stk11 ) , two clinically relevant tumour suppressors , markedly impaired the response of CancerKras-mutant cancers to docetaxel monotherapy .
22425996
We observed that the addition of selumetinib provided substantial benefit for mice with Cancerlung cancer caused by Kras and Kras and p53 mutations , but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy .
22426421
Tyrosine kinase inhibitors ( TKIs ) elicit high response rates among individuals with kinase driven Cancermalignancies , including chronic myeloid leukemia ( CML ) and epidermal growth factor receptor mutated non-small-cell lung cancer ( EGFR NSCLC ) .
22426421
Tyrosine kinase inhibitors ( TKIs ) elicit high response rates among individuals with kinase driven malignancies , including Cancerchronic myeloid leukemia ( CML ) and epidermal growth factor receptor mutated non-small-cell lung cancer ( EGFR NSCLC ) .
22426421
Tyrosine kinase inhibitors ( TKIs ) elicit high response rates among individuals with kinase driven malignancies , including chronic myeloid leukemia ( CML ) and epidermal growth factor receptor mutated Cancernon-small-cell lung cancer ( EGFR NSCLC ) .
22426421
BIM is a pro apoptotic member of the B-cell CLL and Cancerlymphoma 2 ( BCL2 ) family of proteins , and its upregulation is required for TKIs to induce apoptosis in kinase driven cancers .
22426421
BIM is a pro apoptotic member of the B-cell CLL and lymphoma 2 ( BCL2 ) family of proteins , and its upregulation is required for TKIs to induce apoptosis in kinase driven Cancercancers .
22430270
PURPOSE : The tet oncogene family member 2 ( TET2 ) gene was recently identified to be mutated in Diseasemyeloid disorders including acute myeloid leukemia ( AML ) .
22430270
PURPOSE : The tet oncogene family member 2 ( TET2 ) gene was recently identified to be mutated in myeloid disorders including Canceracute myeloid leukemia ( AML ) .
22430270
TET2 ( mut ) did not impact the response to induction therapy and clinical outcome ; the combination of patients who exhibited TET2 ( mut ) and/or IDH ( mut ) revealed shorter overall survival ( P = .03 ) , although this association was not independent from AdverseOutcomeknown risk factors .
22431701
BACKGROUND : Predictive markers of response to chemotherapy are lacking in Cancerbreast cancer patients .
22431701
Forkhead Box Protein 3 ( FOXP3 ) is an anti-oncogene whose absence in Cancercancer cells could confer resistance to DNA damaging agent .
22431701
So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in Cancerbreast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival ( OS ) benefit over anthracyclines alone , in patients with FOXP3 negative tumors .
22431701
So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival ( OS ) benefit over anthracyclines alone , in patients with CancerFOXP3 negative tumors .
22431701
PATIENTS AND METHODS : Expression of FOXP3 in Cancercancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel ( Taxotere ) to anthracyclines in patients with localized breast cancer .
22431701
PATIENTS AND METHODS : Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in Cancertumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel ( Taxotere ) to anthracyclines in patients with localized breast cancer .
22431701
PATIENTS AND METHODS : Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel ( Taxotere ) to anthracyclines in patients with Cancerlocalized breast cancer .
22431701
Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in Cancertumor cells .
22431701
RESULTS : Four hundred and five Cancertumors were found to express FOXP3 ( 37 % ) .
22431701
FOXP3 expression in Cancerbreast cancer cells was associated with better OS ( P = 0.003 ) .
22431701
Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in Cancerbreast cancer cells is independently associated with improved OS in patients treated with anthracycline based adjuvant chemotherapy , but not in patients treated with sequential anthracycline-taxane .
22431701
Moreover , in vitro experiments showed that FOXP3 induction in Cancerbreast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy .
22431701
CONCLUSION : FOXP3 expression in Cancertumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer .
22431701
CONCLUSION : FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in Cancerbreast cancer .
22439647
BACKGROUND : CancerGastrointestinal stromal tumors ( GIST ) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib ( IM ) or sunitinib ( SU ) .
22439647
Arterial hypertension ( AH ) is common adverse event related to SU , reported as predictive factor in Cancerrenal cell carcinoma .
22439647
Patients with Cancerprimary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS ( 68 % and 57 % ; median 65.5 and 50.5 weeks , respectively ) than patients having tumors with KIT exon 11 or PDGFRA mutations ( 34 % and 15 % ; median 36.8 and 9 weeks , respectively ) .
22439647
Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS ( 68 % and 57 % ; median 65.5 and 50.5 weeks , respectively ) than patients having Cancertumors with KIT exon 11 or PDGFRA mutations ( 34 % and 15 % ; median 36.8 and 9 weeks , respectively ) .
22439647
We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis : Cancerprimary tumor genotype and presence of AH .
22439647
The most common adverse events during therapy were : fatigue , AH , hypothyroidism , hand and Diseasefoot syndrome , mucositis , skin reactions , dyspepsia , and diarrhea .
22439647
The most common adverse events during therapy were : fatigue , AH , hypothyroidism , hand and foot syndrome , Diseasemucositis , skin reactions , dyspepsia , and diarrhea .
22439647
Two deaths were assessed as related to Cancertumor rupture caused by reaction to SU therapy .
22439647
The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher AdverseOutcomerisk of hypothyroidism ( OR : 10.0 p = 0.041 and OR : 10.5 ; p = 0.015 , respectively ) .
22439647
CancerPrimary tumor KIT and PDGFRA genotype and SU induced AH , as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS .
22440753
Increased nuclear accumulation of beta-catenin , a mediator of canonical Wnt signaling , is found in Cancernumerous tumors and is frequently associated with tumor progression and metastasis .
22440753
Increased nuclear accumulation of beta-catenin , a mediator of canonical Wnt signaling , is found in numerous tumors and is frequently associated with Cancertumor progression and metastasis .
22440753
Increased nuclear accumulation of beta-catenin , a mediator of canonical Wnt signaling , is found in numerous tumors and is frequently associated with tumor progression and Cancermetastasis .
22440753
In a dose dependent manner , JW55 inhibited canonical Wnt signaling in Cancercolon carcinoma cells that contained mutations in either the APC ( adenomatous polyposis coli ) locus or in an allele of beta-catenin .
22452895
BACKGROUND : Afatinib is an irreversible ErbB family blocker with preclinical activity in Cancernon-small-cell lung cancer ( NSCLC ) with EGFR mutations .
22452895
We aimed to assess the efficacy of afatinib in patients with Cancerlung adenocarcinoma and EGFR mutations .
22452895
METHODS : In this phase 2 study , we enrolled patients from 30 centres in Taiwan and the USA with Cancerlung adenocarcinoma ( stage IIIb with pleural effusion or stage IV ) with EGFR mutations , who had no more than one previous chemotherapy regimen for advanced disease , an Eastern Cooperative Oncology Group performance status of 0-2 , and no previous treatment with EGFR tyrosine kinase inhibitors .
22452895
METHODS : In this phase 2 study , we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma ( stage IIIb with pleural effusion or stage IV ) with EGFR mutations , who had no more than one previous chemotherapy regimen for Diseaseadvanced disease , an Eastern Cooperative Oncology Group performance status of 0-2 , and no previous treatment with EGFR tyrosine kinase inhibitors .
22452895
The primary endpoint was the proportion of patients with a confirmed objective response ( complete response or partial response ) , on the basis of Response Evaluation Criteria in CancerSolid Tumors 1.0 ( independent review ) .
22452895
We recorded one possibly drug related death ( Diseaseinterstitial lung disease ) .
22452895
INTERPRETATION : Afatinib shows activity in the treatment of patients with Canceradvanced lung adenocarcinoma with EGFR mutations , especially in patients with deletion 19 or L858R mutations .
22479427
These findings imply a complex and non linear molecular relationship between PTEN , its regulators and effectors in the tumorigenesis of Cancerglioblastoma .
22479427
Additionally , there is evidence that temozolomide may be more effective in eradicating CancerGBM cancer cells with PTEN loss and hence , level the outcomes between the PTEN retained and loss groups .
22490330
The prevalence , the prognostic effect , and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with Canceracute myeloid leukemia ( AML ) younger than 60 years .
22490330
We conclude that DNMT3A mutation status is an important factor to consider for AdverseOutcomerisk stratification of patients with AML .
22493419
PURPOSE : This is a noncomparative , randomized , phase II trial of preoperative taxane-anthracycline in combination with trastuzumab , lapatinib , or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive , stage II to CancerIIIA operable breast cancer .
22493419
The primary aim was to estimate the percentage of pathologic complete response ( pCR ; no Cancerinvasive tumor in breast and axillary nodes ) .
22493419
Diarrhea and dermatologic and Diseasehepatic toxicities were observed more frequently in patients receiving lapatinib .
22493419
These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of CancerHER2 positive breast cancer .
22504184
Effective targeted Cancercancer therapeutic development depends upon distinguishing disease associated ' driver ' mutations , which have causative roles in malignancy pathogenesis , from ' passenger ' mutations , which are dispensable for cancer initiation and maintenance .
22504184
Effective targeted cancer therapeutic development depends upon distinguishing Diseasedisease associated ' driver ' mutations , which have causative roles in malignancy pathogenesis , from ' passenger ' mutations , which are dispensable for cancer initiation and maintenance .
22504184
Effective targeted cancer therapeutic development depends upon distinguishing disease associated ' driver ' mutations , which have causative roles in Cancermalignancy pathogenesis , from ' passenger ' mutations , which are dispensable for cancer initiation and maintenance .
22504184
Effective targeted cancer therapeutic development depends upon distinguishing disease associated ' driver ' mutations , which have causative roles in malignancy pathogenesis , from ' passenger ' mutations , which are dispensable for Cancercancer initiation and maintenance .
22504184
Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into Cancerhuman cancer biology .
22504184
Activating internal tandem duplication ( ITD ) mutations in FLT3 ( FLT3-ITD ) are detected in approximately 20 % of Diseaseacute myeloid leukaemia ( AML ) patients and are associated with a poor prognosis .
22504184
Activating internal tandem duplication ( ITD ) mutations in FLT3 ( FLT3-ITD ) are detected in approximately 20 % of acute myeloid leukaemia ( AML ) patients and are associated with a AdverseOutcomepoor prognosis .
22541434
CancerNon small cell lung cancer ( NSCLC ) is the most frequent cause of cancer deaths worldwide ; nearly half contain mutations in the receptor tyrosine kinase and RAS pathway .
22541434
Non small cell lung cancer ( NSCLC ) is the most frequent cause of Cancercancer deaths worldwide ; nearly half contain mutations in the receptor tyrosine kinase and RAS pathway .
22541434
In a Kras driven NSCLC mouse model , Gata2 loss dramatically reduced Cancertumor development .
22541434
Furthermore , Gata2 deletion in Cancerestablished Kras mutant tumors induced striking regression .
22541434
Although GATA2 itself is likely undruggable , combined suppression of GATA2 regulated pathways with clinically approved inhibitors caused Cancermarked tumor clearance .
22541434
Discovery of the nononcogene addiction of CancerKRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation .
22544540
For Cancerbreast cancer patients with lymph node metastasis , paclitaxel is the first-line chemotherapy drug .
22544540
For breast cancer patients with Cancerlymph node metastasis , paclitaxel is the first-line chemotherapy drug .
22544540
Clinical studies showed that some patients with Cancerbreast cancer were insensitive to paclitaxel , which led to chemotherapy failure .
22544540
Epidemiological studies have also associated Cancerelevated tumor tissue TIMP-1 levels with a poor response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline based chemotherapy .
22544540
Additionally , our previous study proved that TIMP-1 significantly decreased the sensitivity of Cancerbreast cancer cells to paclitaxel induced apoptosis by enhancing degradation of cyclin B1 .
22544540
In this retrospective study , we investigated the association between expression levels of TIMP-1 protein in the Cancerprimary tumor and objective response to paclitaxel based chemotherapy in 99 patients with breast cancer .
22544540
In this retrospective study , we investigated the association between expression levels of TIMP-1 protein in the primary tumor and objective response to paclitaxel based chemotherapy in 99 patients with Cancerbreast cancer .
22544540
Our data showed that Cancerelevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel based chemotherapy , and TIMP-1 might be a potential biomarker for predicting response of breast cancer patients to paclitaxel based chemotherapy .
22544540
Our data showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel based chemotherapy , and TIMP-1 might be a potential biomarker for predicting response of Cancerbreast cancer patients to paclitaxel based chemotherapy .
22550175
The Sonic Hedgehog ( Shh ) pathway drives a subset of Cancermedulloblastomas , a malignant neuroectodermal brain cancer , and other cancers .
22550175
The Sonic Hedgehog ( Shh ) pathway drives a subset of medulloblastomas , a Cancermalignant neuroectodermal brain cancer , and other cancers .
22550175
The Sonic Hedgehog ( Shh ) pathway drives a subset of medulloblastomas , a malignant neuroectodermal brain cancer , and Cancerother cancers .
22550175
Small-molecule Shh pathway inhibitors have induced Cancertumor regression in mice and patients with medulloblastoma ; however , drug resistance rapidly emerges , in some cases via de novo mutation of the drug target .
22550175
Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with Cancermedulloblastoma ; however , drug resistance rapidly emerges , in some cases via de novo mutation of the drug target .
22550175
Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh driven Cancermouse medulloblastoma model .
22550175
In this model , saridegib treatment induced Cancertumor reduction and significantly prolonged survival .
22550175
Furthermore , the effect of saridegib on Cancertumor initiating capacity was demonstrated by reduced tumor incidence , slower growth , and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors .
22550175
Furthermore , the effect of saridegib on tumor initiating capacity was demonstrated by reduced Cancertumor incidence , slower growth , and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors .
22550175
Furthermore , the effect of saridegib on tumor initiating capacity was demonstrated by reduced tumor incidence , slower growth , and Cancerspontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors .
22550175
Furthermore , the effect of saridegib on tumor initiating capacity was demonstrated by reduced tumor incidence , slower growth , and spontaneous tumor regression that occurred in allografts generated from previously treated Cancerautochthonous medulloblastomas compared with those from untreated donors .
22550175
Saridegib , a known P-glycoprotein ( Pgp ) substrate , induced Pgp activity in Cancertreated tumors , which likely contributed to emergence of drug resistance .
22551904
INTRODUCTION : Elevated DNA-repair capacity has been related to chemoresistance of platinum doublet chemotherapy in Cancernon-small-cell lung cancer ( NSCLC ) .
22586653
Only a fraction of patients with Cancermetastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor ( EGFR ) antibodies , which calls for the identification of novel biomarkers for better personalized medicine .
22586653
We produced large xenograft cohorts from 85 patient derived , genetically characterized Cancermetastatic colorectal cancer samples ( " xenopatients " ) to discover novel determinants of therapeutic response and new oncoprotein targets .
22586653
Serially passaged Cancertumors retained the morphologic and genomic features of their original counterparts .
22586653
A proof-of-concept , multiarm study in HER2 amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt , Cancerlong lasting tumor regression .
22586653
Our results suggest promising therapeutic opportunities in cetuximab resistant patients with Cancermetastatic colorectal cancer , whose medical treatment in the chemorefractory setting remains an unmet clinical need.SIGNIFICANCE : Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin , combining the flexibility of preclinical analysis with the informative value of population based studies .
22586653
Our results suggest promising therapeutic opportunities in cetuximab resistant patients with metastatic colorectal cancer , whose medical treatment in the chemorefractory setting remains an unmet clinical need.SIGNIFICANCE : Direct transfer xenografts of Cancertumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin , combining the flexibility of preclinical analysis with the informative value of population based studies .
22586653
Our results suggest promising therapeutic opportunities in cetuximab resistant patients with metastatic colorectal cancer , whose medical treatment in the chemorefractory setting remains an unmet clinical need.SIGNIFICANCE : Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the Cancertumors of origin , combining the flexibility of preclinical analysis with the informative value of population based studies .
22586653
Our suite of patient derived xenografts from Cancermetastatic colorectal carcinomas reliably mimicked disease response in humans , prospectively recapitulated biomarker based case stratification , and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting .
22586653
Our suite of patient derived xenografts from metastatic colorectal carcinomas reliably mimicked Diseasedisease response in humans , prospectively recapitulated biomarker based case stratification , and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting .
22586653
Our suite of patient derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans , prospectively recapitulated biomarker based case stratification , and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this Cancertumor setting .
22591296
BACKGROUND : CancerT-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+ CD8+ cytotoxic T lymphocytes ( CTLs ) and often associated with autoimmune disorders and immune mediated cytopenias .
22591296
BACKGROUND : T-cell large granular lymphocytic leukemia is a Diseaserare lymphoproliferative disorder characterized by the expansion of clonal CD3+ CD8+ cytotoxic T lymphocytes ( CTLs ) and often associated with autoimmune disorders and immune mediated cytopenias .
22591296
BACKGROUND : T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+ CD8+ cytotoxic T lymphocytes ( CTLs ) and often associated with Diseaseautoimmune disorders and immune mediated cytopenias .
22591296
BACKGROUND : T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+ CD8+ cytotoxic T lymphocytes ( CTLs ) and often associated with autoimmune disorders and Diseaseimmune mediated cytopenias .
22591296
METHODS : We used next generation exome sequencing to identify somatic mutations in CTLs from an index patient with Cancerlarge granular lymphocytic leukemia .
22591296
Targeted resequencing was performed in a well characterized cohort of 76 patients with this Diseasedisorder , characterized by clonal T-cell-receptor rearrangements and increased numbers of large granular lymphocytes .
22591296
RESULTS : Mutations in the signal transducer and activator of transcription 3 gene ( STAT3 ) were found in 31 of 77 patients ( 40 % ) with Cancerlarge granular lymphocytic leukemia .
22591296
Patients with STAT3 mutations presented more often with Diseaseneutropenia and rheumatoid arthritis than did patients without these mutations .
22591296
Patients with STAT3 mutations presented more often with neutropenia and Diseaserheumatoid arthritis than did patients without these mutations .
22591296
CONCLUSIONS : The SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with Cancerlarge granular lymphocytic leukemia ; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this disease .
22591296
CONCLUSIONS : The SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with large granular lymphocytic leukemia ; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this Diseasedisease .
22596232
BACKGROUND : CancerHepatocellular carcinoma ( HCC ) ranks as the third leading cause of cancer deaths worldwide .
22596232
BACKGROUND : Hepatocellular carcinoma ( HCC ) ranks as the third leading cause of Cancercancer deaths worldwide .
22608338
We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with Cancerincurable solid tumours , especially those with melanoma and untreated , asymptomatic brain metastases .
22608338
We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours , especially those with Cancermelanoma and untreated , asymptomatic brain metastases .
22608338
Eligible patients had Cancerincurable solid tumours , were 18 years or older , and had adequate organ function .
22608338
Efficacy at the recommended phase 2 dose was studied in patients with CancerBRAF-mutant tumours , including those with non Val600Glu mutations , in three cohorts : metastatic melanoma , melanoma with untreated brain metastases , and non melanoma solid tumours .
22608338
Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours , including those with non Val600Glu mutations , in three cohorts : Cancermetastatic melanoma , melanoma with untreated brain metastases , and non melanoma solid tumours .
22608338
Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours , including those with non Val600Glu mutations , in three cohorts : metastatic melanoma , Cancermelanoma with untreated brain metastases , and non melanoma solid tumours .
22608338
Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours , including those with non Val600Glu mutations , in three cohorts : metastatic melanoma , melanoma with untreated brain metastases , and Cancernon melanoma solid tumours .
22608338
FINDINGS : We enrolled 184 patients , of whom 156 had Cancermetastatic melanoma .
22608338
The most common treatment related adverse events of grade 2 or worse were Cancercutaneous squamous-cell carcinoma ( 20 patients , 11 % ) , fatigue ( 14 , 8 % ) , and pyrexia ( 11 , 6 % ) .
22608338
At the recommended phase 2 dose in 36 patients with CancerVal600 BRAF-mutant melanoma , responses were reported in 25 ( 69 % , 95 % CI 51.9-83 .7 ) and confirmed responses in 18 ( 50 % , 32.9-67 .1 ) .
22608338
21 ( 78 % , 57.7-91 .4 ) of 27 patients with CancerVal600Glu BRAF-mutant melanoma responded and 15 ( 56 % , 35.3-74 .5 ) had a confirmed response .
22608338
In CancerVal600 BRAF-mutant melanoma , responses were durable , with 17 patients ( 47 % ) on treatment for more than 6 months .
22608338
In patients with Cancermelanoma and untreated brain metastases , nine of ten patients had reductions in size of brain lesions .
22608338
In 28 patients with CancerBRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a gastrointestinal stromal tumour , papillary thyroid cancers , non-small-cell lung cancer , ovarian cancer , and colorectal cancer .
22608338
In 28 patients with BRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a Cancergastrointestinal stromal tumour , papillary thyroid cancers , non-small-cell lung cancer , ovarian cancer , and colorectal cancer .
22608338
In 28 patients with BRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a gastrointestinal stromal tumour , Cancerpapillary thyroid cancers , non-small-cell lung cancer , ovarian cancer , and colorectal cancer .
22608338
In 28 patients with BRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a gastrointestinal stromal tumour , papillary thyroid cancers , Cancernon-small-cell lung cancer , ovarian cancer , and colorectal cancer .
22608338
In 28 patients with BRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a gastrointestinal stromal tumour , papillary thyroid cancers , non-small-cell lung cancer , Cancerovarian cancer , and colorectal cancer .
22608338
In 28 patients with BRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a gastrointestinal stromal tumour , papillary thyroid cancers , non-small-cell lung cancer , ovarian cancer , and Cancercolorectal cancer .
22608338
INTERPRETATION : Dabrafenib is safe in patients with Cancersolid tumours , and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma , brain metastases , and other solid tumours .
22608338
INTERPRETATION : Dabrafenib is safe in patients with solid tumours , and an active inhibitor of Val600-mutant BRAF with responses noted in patients with Cancermelanoma , brain metastases , and other solid tumours .
22608338
INTERPRETATION : Dabrafenib is safe in patients with solid tumours , and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma , brain metastases , and Cancerother solid tumours .
22616558
Recurrent mutations of isocitrate dehydrogenase isoforms 1 and 2 ( IDH1 and IDH2 ) have recently been studied in adult patients with Canceracute myeloid leukemia ( AML ) .
22616558
Screening of IDH1/2 mutations could help to identify patients at AdverseOutcomehigh risk within some subsets of AML .
22619677
Depending on the Cancertumour type , genetic alterations resulting in the functional inactivation have frequently been reported in both genes .
22619677
By contrast , much less is known regarding the overexpression of these proteins in the Cancertumor cells .
22619677
In this study , expressions of p16 ( INK4 ) RB1 , and CDKN2A copy number variances ( CNV ) in the Cancertumor cells were assessed by immunohistochemistry and fluorescence in situ hybridization ( FISH ) , respectively , in 73 nonsmall cell lung cancer ( NSCLC ) with known 5-year survivals .
22619677
In this study , expressions of p16 ( INK4 ) RB1 , and CDKN2A copy number variances ( CNV ) in the tumor cells were assessed by immunohistochemistry and fluorescence in situ hybridization ( FISH ) , respectively , in 73 Cancernonsmall cell lung cancer ( NSCLC ) with known 5-year survivals .
22619677
Therefore , among the molecular genetic prognostic factors , expressions of RB1 and p16 ( INK4 ) in the Cancertumor cells were the most strongly predictive of adverse outcomes in stage I and II nonsquamous NSCLC .
22623731
PURPOSE : To characterize the importance of cellular Fas associated death domain ( FADD )-like interleukin 1beta converting enzyme ( FLICE ) inhibitory protein ( c-FLIP ) , a key regulator of caspase-8 ( FLICE )-promoted apoptosis , in modulating the response of Cancerprostate cancer cells to androgen receptor ( AR )-targeted therapy .
22623731
RESULTS : c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and Cancerprostate cancer tissue relative to normal prostate epithelium ( P < 0.001 ) .
22623731
Maximal c-FLIP expression was detected in Cancercastrate resistant prostate cancer ( CRPC ; P < 0.001 ) .
22623731
CONCLUSION : c-FLIP reduces the efficacy of AR targeted therapy and maintains the viability of Cancerprostate cancer cells .
22623731
A combination of HDACi with androgen deprivation therapy may be effective in Diseaseearly-stage disease , using c-FLIP expression as a predictive biomarker of sensitivity .
22628360
PTEN : Cancerhamartoma tumor syndrome ( PHTS ) is a group of syndromes caused by mutations in PTEN .
22628360
PTEN : Diseasehamartoma tumor syndrome ( PHTS ) is a group of syndromes caused by mutations in PTEN .
22628360
PTEN : hamartoma tumor syndrome ( PHTS ) is a group of Diseasesyndromes caused by mutations in PTEN .
22650231
BACKGROUND : Many studies on Cancerthyroid follicular tumors have reported the presence of somatic mutations to three forms of RAS : HRAS , KRAS , and NRAS .
22650231
To clarify the significance of RAS mutations , we examined a large number of Cancerfollicular adenomas and carcinomas obtained from a single institute using established methods for the analysis of RAS .
22650231
To clarify the significance of RAS mutations , we examined a large number of follicular adenomas and Cancercarcinomas obtained from a single institute using established methods for the analysis of RAS .
22650231
METHODS : CancerTumor samples from 40 follicular adenoma and 58 follicular carcinoma patients treated at the Kanagawa Cancer Center Hospital were analyzed .
22650231
METHODS : Tumor samples from 40 Cancerfollicular adenoma and 58 follicular carcinoma patients treated at the Kanagawa Cancer Center Hospital were analyzed .
22650231
METHODS : Tumor samples from 40 follicular adenoma and 58 Cancerfollicular carcinoma patients treated at the Kanagawa Cancer Center Hospital were analyzed .
22650231
RESULTS : Twelve out of 40 ( 30 % ) Canceradenomas harbored RAS mutations .
22650231
In contrast , 33 out of 58 ( 57 % ) Cancerfollicular carcinomas harbored RAS mutations , and the mutation was predominantly found in the NRAS codon 61 ( 22/33 , 67 % , p < 0.01 ) .
22650231
The rate of gene mutations was significantly higher in the Cancercarcinomas than in the adenomas ( p < 0.01 ) .
22650231
The rate of gene mutations was significantly higher in the carcinomas than in the Canceradenomas ( p < 0.01 ) .
22650231
The NRAS codon 61 mutation in Cancerfollicular carcinomas was positively associated with distant metastases through the entire clinical course of the patients ( p < 0.05 ) , and RAS mutations were associated with poor overall patient survival ( p < 0.05 ) .
22650231
CONCLUSIONS : We investigated the frequency of RAS mutations in Cancerfollicular thyroid tumors from a large number of cases obtained from a single institute .
22650231
The predominance of NRAS codon 61 mutations as a feature of Cancercarcinomas indicates that the diagnosis of adenoma alongside the presence of this mutation should be made cautiously .
22650231
The predominance of NRAS codon 61 mutations as a feature of carcinomas indicates that the diagnosis of Canceradenoma alongside the presence of this mutation should be made cautiously .
22650231
Our study raises the possibility that Cancerfollicular adenomas with the RAS mutations have an inherent malignant potential ; however , the clinical significance of this finding should be further investigated in more patients and over a longer follow-up period .
22658127
METHODS : We enrolled patients with Canceradvanced melanoma , non-small-cell lung cancer , castration resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks .
22658127
METHODS : We enrolled patients with advanced melanoma , Cancernon-small-cell lung cancer , castration resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks .
22658127
METHODS : We enrolled patients with advanced melanoma , non-small-cell lung cancer , Cancercastration resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks .
22658127
METHODS : We enrolled patients with advanced melanoma , non-small-cell lung cancer , castration resistant prostate cancer , or renal-cell or Cancercolorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks .
22658127
Patients received up to 12 cycles until Diseasedisease progression or a complete response occurred .
22658127
Grade 3 or 4 drug related adverse events occurred in 14 % of patients ; there were three deaths from Diseasepulmonary toxicity .
22658127
Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with Cancernon-small-cell lung cancer , melanoma , or renal-cell cancer .
22658127
Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , Cancermelanoma , or renal-cell cancer .
22658127
Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or Cancerrenal-cell cancer .
22658127
Cumulative response rates ( all doses ) were 18 % among patients with Cancernon-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) .
22658127
Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with Cancermelanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) .
22658127
Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with Cancerrenal-cell cancer ( 9 of 33 patients ) .
22658127
To assess the role of intratumoral PD-1 ligand ( PD-L1 ) expression in the modulation of the PD-1-PD-L1 pathway , immunohistochemical analysis was performed on Cancerpretreatment tumor specimens obtained from 42 patients .
22658127
Of 17 patients with CancerPD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P = 0.006 ) .
22658127
Of 17 patients with PD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with CancerPD-L1-positive tumors had an objective response ( P = 0.006 ) .
22658127
CONCLUSIONS : Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with Cancernon-small-cell lung cancer , melanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use .
22658127
CONCLUSIONS : Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , Cancermelanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use .
22658127
CONCLUSIONS : Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , melanoma , or Cancerrenal-cell cancer ; the adverse-event profile does not appear to preclude its use .
22658127
Preliminary data suggest a relationship between PD-L1 expression on Cancertumor cells and objective response .
22663011
BACKGROUND : Activating mutations in serine threonine protein kinase B-RAF ( BRAF ) are found in 50 % of patients with Canceradvanced melanoma .
22663011
METHODS : In this phase 3 open-label trial , we randomly assigned 322 patients who had Cancermetastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib , an oral selective MEK inhibitor , or chemotherapy in a 2:1 ratio .
22663011
Patients in the chemotherapy group who had Diseasedisease progression were permitted to cross over to receive trametinib .
22663011
RESULTS : Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group ( hazard ratio for Diseasedisease progression or death in the trametinib group , 0.45 ; 95 % confidence interval [ CI ] , 0.33 to 0.63 ; P < 0.001 ) .
22663011
CONCLUSIONS : Trametinib , as compared with chemotherapy , improved rates of progression-free and overall survival among patients who had Cancermetastatic melanoma with a BRAF V600E or V600K mutation .
22682017
AIMS : A minority of patients with Canceradvanced sarcoma achieve prolonged progression free survival ( PFS ) with insulin growth factor type 1 receptor ( IGF-1R ) monoclonal antibody ( Ab ) therapy .
22682017
METHODS : This single centre series includes patients with unresectable or Cancermetastatic soft tissue sarcomas ( STS ) , Ewing sarcoma ( ES ) and osteosarcoma treated with IGF-1R Ab ( R1507 , IMC-A12 , SCH 717454 and CP-751 .871 ) in the Centre Leon Berard .
22682017
METHODS : This single centre series includes patients with unresectable or metastatic soft tissue sarcomas ( STS ) , CancerEwing sarcoma ( ES ) and osteosarcoma treated with IGF-1R Ab ( R1507 , IMC-A12 , SCH 717454 and CP-751 .871 ) in the Centre Leon Berard .
22682017
METHODS : This single centre series includes patients with unresectable or metastatic soft tissue sarcomas ( STS ) , Ewing sarcoma ( ES ) and Cancerosteosarcoma treated with IGF-1R Ab ( R1507 , IMC-A12 , SCH 717454 and CP-751 .871 ) in the Centre Leon Berard .
22682017
CancerTumour samples were analysed by immunohistochemistry for expression of IGF-1R , insulin like growth factor binding protein type 3 ( IGFBP-3 ) , Ki67 , epidermal growth factor receptor ( HER1 ) and human epidermal growth factor receptor 2 ( HER2 ) .
22682017
RESULTS : All Cancertumour samples had a positive IGF-1R immunostaining on 60 % to 100 % of tumour cells .
22682017
RESULTS : All tumour samples had a positive IGF-1R immunostaining on 60 % to 100 % of Cancertumour cells .
22682017
Nuclear localisation of IGF-1R in Cancertumour cells might be a hallmark of pathway activation .
22698404
Studies on the role of TP53 mutation in Cancerbreast cancer response to chemotherapy are conflicting .
22698404
Here , we show that , contrary to dogma , CancerMMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53 .
22698404
Here , we show that , contrary to dogma , MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to Cancertumors with wild-type p53 .
22698404
Doxorubicin treated Cancerp53 mutant tumors failed to arrest proliferation , leading to abnormal mitoses and cell death , whereas p53 wild-type tumors arrested , avoiding mitotic catastrophe .
22698404
Doxorubicin treated p53 mutant tumors failed to arrest proliferation , leading to abnormal mitoses and cell death , whereas Cancerp53 wild-type tumors arrested , avoiding mitotic catastrophe .
22698404
CancerSenescent tumor cells persisted , secreting senescence associated cytokines exhibiting autocrine and paracrine activity and mitogenic potential .
22698404
Thus , we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in Cancercancer therapy .
22699455
Despite AdverseOutcomerisk adapted treatment , survival of children with relapse of acute lymphoblastic leukemia ( ALL ) remains poor compared with that of patients with initial diagnosis of ALL .
22699455
Despite risk adapted treatment , survival of children with relapse of Canceracute lymphoblastic leukemia ( ALL ) remains poor compared with that of patients with initial diagnosis of ALL .
22699455
CancerLeukemia associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies .
22699455
Next , we investigated how both alterations can improve the AdverseOutcomeestablished risk stratification in relapsed ALL .
22699455
Intermediate-risk relapse patients with Diseaselow minimal residual disease are currently considered to have a good prognosis .
22699455
We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in AdverseOutcomefuture risk assessment of children with relapsed ALL to indicate treatment intensification or intervention .
22745105
PURPOSE : To determine the potential of crenolanib , a potent inhibitor of PDGFRA , to treat Cancermalignancies driven by mutant PDGFRA .
22745105
EXPERIMENTAL DESIGN : The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models , including Cancerprimary gastrointestinal stromal tumors ( GIST ) cells .
22753902
PURPOSE : To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) and with gene and microRNA expression signatures .
22753902
PATIENTS AND METHODS : Younger ( < 60 years ; n = 175 ) and older ( > = 60 years ; n = 225 ) patients with CN-AML treated with intensive cytarabine and anthracycline based first-line therapy on CancerCancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations .
22753902
PATIENTS AND METHODS : Younger ( < 60 years ; n = 175 ) and older ( > = 60 years ; n = 225 ) patients with CN-AML treated with intensive cytarabine and anthracycline based first-line therapy on Cancer and DiseaseLeukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations .
22798288
Kinase inhibitors are accepted treatment for Cancermetastatic melanomas that harbor specific driver mutations in BRAF or KIT , but only 40 % to 50 % of cases are positive .
22798288
To uncover other potential targetable mutations , we conducted whole-genome sequencing of a highly aggressive BRAF ( V600 ) and KIT ( W557 , V559 , L576 , K642 , and D816 ) Cancerwild-type melanoma .
22798288
Analysis of BRAF exon 15 in 49 Cancertumors negative for BRAF ( V600 ) mutations as well as driver mutations in KIT , NRAS , GNAQ , and GNA11 , showed that two ( 4 % ) harbored L597 mutations and another two involved BRAF D594 and K601 mutations .
22798288
A patient with BRAF ( L597S ) Cancermutant metastatic melanoma responded significantly to treatment with the MEK inhibitor , TAK-733 .
22798288
Collectively , these data show clinical significance to BRAF ( L597 ) mutations in melanoma.SIGNIFICANCE : This study shows that cells harboring BRAF ( L597R ) mutants are sensitive to MEK inhibitor treatment , providing a rationale for routine screening and therapy of BRAF ( CancerL597R )-mutant melanoma .
22802530
Here , we show that genetic ablation of p110alpha blocks Cancertumor formation in both polyoma middle T antigen ( MT ) and HER2 and Neu transgenic models of breast cancer .
22802530
Here , we show that genetic ablation of p110alpha blocks tumor formation in both Cancerpolyoma middle T antigen ( MT ) and HER2 and Neu transgenic models of breast cancer .
22802530
Here , we show that genetic ablation of p110alpha blocks tumor formation in both polyoma middle T antigen ( MT ) and HER2 and Neu transgenic models of Cancerbreast cancer .
22802530
Our findings demonstrate a novel p110beta based regulatory role in receptor mediated PI3K activity and identify p110alpha as an important target for treatment of DiseaseHER2 positive disease .
22805291
We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety , pharmacokinetics , pharmacodynamics , and response rate in individuals with Canceradvanced solid tumours .
22805291
METHODS : We undertook a multicentre phase 1 study in patients with Canceradvanced solid tumours and adequate organ function .
22805291
Blood samples and Cancertumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes .
22805291
Adverse events were defined with Diseasecommon toxicity criteria , and tumour response was measured by Response Evaluation Criteria In Solid Tumors .
22805291
Adverse events were defined with common toxicity criteria , and Cancertumour response was measured by Response Evaluation Criteria In Solid Tumors .
22805291
Adverse events were defined with common toxicity criteria , and tumour response was measured by Response Evaluation Criteria In CancerSolid Tumors .
22805291
The most common treatment related adverse events were rash or Diseasedermatitis acneiform ( n = 165 ; 80 % ) and diarrhoea ( 87 ; 42 % ) , most of which were grade 1 and 2 .
22805292
BACKGROUND : MEK is a member of the MAPK signalling cascade that is commonly activated in Cancermelanoma .
22805292
We aimed to analyse safety , efficacy , and genotyping data for the oral , small-molecule MEK inhibitor trametinib in patients with Cancermelanoma .
22805292
The main results of this study are reported elsewhere ; here we present data relating to patients with Cancermelanoma .
22805292
We obtained Cancertumour samples to assess BRAF mutational status , and available tissues underwent exploratory genotyping analysis .
22805292
DiseaseDisease response was measured by Response Evaluation Criteria in Solid Tumors , and adverse events were defined by common toxicity criteria .
22805292
Disease response was measured by Response Evaluation Criteria in CancerSolid Tumors , and adverse events were defined by common toxicity criteria .
22805292
Disease response was measured by Response Evaluation Criteria in Solid Tumors , and adverse events were defined by Diseasecommon toxicity criteria .
22805292
FINDINGS : 97 patients with Cancermelanoma were enrolled , including 81 with cutaneous or unknown primary melanoma ( 36 BRAF mutant , 39 BRAF wild-type , six BRAF status unknown ) , and 16 with uveal melanoma .
22805292
FINDINGS : 97 patients with melanoma were enrolled , including 81 with cutaneous or Cancerunknown primary melanoma ( 36 BRAF mutant , 39 BRAF wild-type , six BRAF status unknown ) , and 16 with uveal melanoma .
22805292
FINDINGS : 97 patients with melanoma were enrolled , including 81 with cutaneous or unknown primary melanoma ( 36 BRAF mutant , 39 BRAF wild-type , six BRAF status unknown ) , and 16 with Canceruveal melanoma .
22805292
The most common treatment related adverse events were rash or Diseasedermatitis acneiform ( n = 80 ; 82 % ) and diarrhoea ( 44 ; 45 % ) , most of which were grade 2 or lower .
22805292
No Cancercutaneous squamous-cell carcinomas were recorded .
22805292
Of 39 patients with CancerBRAF wild-type melanoma , four partial responses were confirmed ( confirmed response rate , 10 % ) .
22805292
INTERPRETATION : Our data show substantial clinical activity of trametinib in Cancermelanoma and suggest that MEK is a valid therapeutic target .
22810899
BACKGROUND : CancerLung adenocarcinomas can be distinguished by identifying mutated driver oncogenes , including epidermal growth factor receptor ( EGFR ) and KRAS .
22810899
For the current report , the authors examined the association of EGFR and KRAS mutations with survival among patients with Canceradvanced lung adenocarcinomas .
22810899
METHODS : Data were analyzed from patients with Canceradvanced lung adenocarcinomas who had known EGFR and KRAS mutation status evaluated between 2002 and 2009 .
22810899
Overall survival from the diagnosis of Diseaseadvanced disease was analyzed using Kaplan-Meier and Cox proportional hazard methods .
22810899
CONCLUSIONS : KRAS mutations predicted shorter survival for patients with Canceradvanced lung adenocarcinomas .
22810899
The presence of EGFR and KRAS mutations define distinct subsets of patients with Cancerlung adenocarcinomas and should be determined in patients when they are diagnosed with advanced disease .
22810899
The presence of EGFR and KRAS mutations define distinct subsets of patients with lung adenocarcinomas and should be determined in patients when they are diagnosed with Diseaseadvanced disease .
22842582
Trastuzumab is effective in about half of CancerHER2 positive breast cancer patients .
22842582
We evaluated the relationship between expression , activation and subcellular localization of selected Akt isoforms and response to trastuzumab based anti-HER2 targeted therapy in patients with CancerHER2 positive metastatic breast cancer .
22842582
Seventy-four women with verified CancerHER2 positive breast cancer were treated with trastuzumab for metastatic disease .
22842582
Seventy-four women with verified HER2 positive breast cancer were treated with trastuzumab for Diseasemetastatic disease .
22842582
Even though Akt isoforms were expressed in the majority of Cancertumours , activated Akt ( pAkt ) was present in the cytoplasm only and not in the nucleus in > 20 % of tumours , and there was no pAkt at all in another 7-13 % of tumours .
22842582
Even though Akt isoforms were expressed in the majority of tumours , activated Akt ( pAkt ) was present in the cytoplasm only and not in the nucleus in > 20 % of Cancertumours , and there was no pAkt at all in another 7-13 % of tumours .
22842582
Even though Akt isoforms were expressed in the majority of tumours , activated Akt ( pAkt ) was present in the cytoplasm only and not in the nucleus in > 20 % of tumours , and there was no pAkt at all in another 7-13 % of Cancertumours .
22842582
Patients whose Cancertumours showed strong Akt2 expression and had pAkt ( pAkt-Thr308 and/or pAkt-Ser473 ) detectable in the cytoplasm as well as nucleus ( n+ c ) , exhibited improved time to progression ( TTP ) and overall survival from the initiation of trastuzumab therapy ( OSt ) .
22842582
Patients with Cancertumours with strong Akt2 and pAkt Thr308 ( n+ c ) had superior TTP ( 17.0 vs. 7.6 months , P = 0.024 ; HR 0.52 ) and OSt ( 51.8 vs. 16.8 months , P = 0.0009 ; HR 0.34 ) compared to other tumours .
22842582
Patients with tumours with strong Akt2 and pAkt Thr308 ( n+ c ) had superior TTP ( 17.0 vs. 7.6 months , P = 0.024 ; HR 0.52 ) and OSt ( 51.8 vs. 16.8 months , P = 0.0009 ; HR 0.34 ) compared to Cancerother tumours .
22842582
This study is the first to prove the significance of Akt kinase isoform , activity and compartmentalization for the prediction of response to trastuzumab based therapy in patients with CancerHER2 positive metastatic breast cancer .
22896685
CancerHigh-grade serous cancer ( HGSC ) , the most common subtype of ovarian cancer , often becomes resistant to chemotherapy , leading to poor patient outcomes .
22896685
High-grade serous cancer ( HGSC ) , the most common subtype of Cancerovarian cancer , often becomes resistant to chemotherapy , leading to poor patient outcomes .
22896685
Intratumoral heterogeneity occurs in nearly all Cancersolid cancers , including ovarian cancer , contributing to the development of resistance mechanisms .
22896685
Intratumoral heterogeneity occurs in nearly all solid cancers , including Cancerovarian cancer , contributing to the development of resistance mechanisms .
22896685
We documented regions of differential DNA copy number between Cancermultiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion .
22896685
In the paired primary and relapse cohort , we observed a greater degree of genomic change in Cancertumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy .
22896685
In the paired primary and relapse cohort , we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with Cancertumors from patients that were resistant to primary chemotherapy .
22896685
Together , our findings underscore the large degree of variation in DNA copy number in spatially and temporally Cancerseparated tumors in HGSC patients , and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients .
22906996
OBJECTIVE : The aim of this study was to elucidate clinical implications of ABCB1 , FCGR2A , and FCGR3A polymorphisms in patients with CancerHER2 positive metastatic breast cancer ( MBC ) after taxane plus trastuzumab ( TH ) chemotherapy .
22912387
PURPOSE : CancerALK rearrangement positive lung cancers can be effectively treated with ALK inhibitors .
22912387
CONCLUSIONS : Our results might explain some of the heterogeneous responses of CancerALK positive tumors to ALK kinase inhibition observed in the clinic .
22912387
Thus , targeted therapy of CancerALK positive lung cancer should take into account the precise ALK genotype .
22912387
Furthermore , combining ALK and HSP90 inhibitors might enhance Cancertumor shrinkage in EML4-ALK-driven tumors .
22912387
Furthermore , combining ALK and HSP90 inhibitors might enhance tumor shrinkage in CancerEML4-ALK-driven tumors .
22923433
CancerCancer drugs often induce dramatic responses in a small minority of patients .
22923433
We used whole-genome sequencing to investigate the genetic basis of a durable remission of Cancermetastatic bladder cancer in a patient treated with everolimus , a drug that inhibits the mTOR ( mammalian target of rapamycin ) signaling pathway .
22923433
Targeted sequencing revealed TSC1 mutations in about 8 % of 109 Canceradditional bladder cancers examined , and TSC1 mutation correlated with everolimus sensitivity .
22931316
BACKGROUND : Waldenstrom 's Diseasemacroglobulinemia is an incurable , IgM secreting lymphoplasmacytic lymphoma ( LPL ) .
22931316
BACKGROUND : Waldenstrom 's macroglobulinemia is an incurable , IgM secreting Cancerlymphoplasmacytic lymphoma ( LPL ) .
22931316
The underlying mutation in this Diseasedisorder has not been delineated .
22931316
METHODS : We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenstrom 's Diseasemacroglobulinemia , with paired normal-tissue and tumor-tissue sequencing in 10 patients .
22931316
Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL , those with Diseaseother B-cell disorders that have some of the same features as LPL , and healthy donors .
22931316
RESULTS : Among the patients with Waldenstrom 's Diseasemacroglobulinemia , a somatic variant ( T -- > C ) in LPL cells was identified at position 38182641 at 3p22 .2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples .
22931316
Sanger sequencing identified MYD88 L265P in Cancertumor samples from 49 of 54 patients with Waldenstrom 's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL ( 91 % of all patients with LPL ) .
22931316
Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom 's Diseasemacroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL ( 91 % of all patients with LPL ) .
22931316
MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom 's Diseasemacroglobulinemia or non IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma , marginal-zone lymphoma , or IgM monoclonal gammopathy of unknown significance .
22931316
MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom 's macroglobulinemia or non IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with Cancermultiple myeloma , marginal-zone lymphoma , or IgM monoclonal gammopathy of unknown significance .
22931316
MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom 's macroglobulinemia or non IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma , Cancermarginal-zone lymphoma , or IgM monoclonal gammopathy of unknown significance .
22931316
Inhibition of MYD88 signaling reduced IkappaBalpha and NF-kappaB p65 phosphorylation , as well as NF-kappaB nuclear staining , in Waldenstrom 's Diseasemacroglobulinemia cells expressing MYD88 L265P .
22931316
Somatic variants in ARID1A in 5 of 30 patients ( 17 % ) , leading to a premature stop or frameshift , were also identified and were associated with an Diseaseincreased disease burden .
22931316
In addition , 2 of 3 patients with Waldenstrom 's Diseasemacroglobulinemia who had wild-type MYD88 had somatic variants in MLL2 .
22931316
CONCLUSIONS : MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom 's Diseasemacroglobulinemia that can be useful in differentiating Waldenstrom 's macroglobulinemia and non IgM LPL from B-cell disorders that have some of the same features .
22931316
CONCLUSIONS : MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom 's macroglobulinemia that can be useful in differentiating Waldenstrom 's Diseasemacroglobulinemia and non IgM LPL from B-cell disorders that have some of the same features .
22931316
CONCLUSIONS : MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom 's macroglobulinemia that can be useful in differentiating Waldenstrom 's macroglobulinemia and non IgM LPL from DiseaseB-cell disorders that have some of the same features .
22948721
PURPOSE : This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras ( KRAS ) gene on treatment efficacy in patients with Cancermetastatic colorectal cancer ( mCRC ) .
22948721
Patients with Cancertumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations ( overall survival 23.3 vs. 14-18 months ; hazard ratio 0.66 , range 0.43-1 .03 ) .
22961667
We further identify MAPK1 amplification in an Cancererlotinib resistant EGFR-mutant non small cell lung carcinoma patient .
22983505
In addition , there are no reports that analyze overall survival and prognostic factors according to K-ras mutation status and subtypes in only Cancerunresectable pancreatic cancer ( PC ) determined from tissues obtained by endoscopic ultrasound guided fine-needle aspiration .
22983505
Clinical data collected included sex , age , Eastern Cooperative Oncology Group performance status , carbohydrate antigen ( CA ) 19-9 , Cancerprimary tumor location , stage ( local or metastatic ) according to TNM staging , first-line chemotherapy , K-ras mutation status and subtypes ( G12D , G12V , and G12R ) , and overall survival .
22983505
CONCLUSIONS : K-ras mutation status and subtypes may be associated with survival duration in Cancerpancreatic cancer patients .
23014527
PURPOSE : The molecular epidemiology of most EGFR and KRAS mutations in Cancerlung cancer remains unclear .
23014527
EXPERIMENTAL DESIGN : We genotyped 3,026 Cancerlung adenocarcinomas for the major EGFR ( exon 19 deletions and L858R ) and KRAS ( G12 , G13 ) mutations and examined correlations with demographic , clinical , and smoking history data .
23014527
Among former smokers with Cancerlung cancer , multivariate analysis showed that , independent of pack-years , increasing smoking-free years raise the likelihood of EGFR mutation .
23014527
CONCLUSIONS : The distinct types of KRAS mutations in smokers versus never smokers suggest that Cancermost KRAS-mutant lung cancers in never smokers are not due to second-hand smoke exposure .
23018865
We aimed at evaluating ASXL1mut in 740 AML with AdverseOutcomeintermediate risk karyotype for frequency , association with other mutations and impact on outcome .
23018865
Five hundred fifty-three cases had a normal karyotype ( NK ) and 187 had AdverseOutcomeintermediate risk aberrant cytogenetics .
23018865
They were associated with higher age ( median : 71.8 vs 61.8 , P < 0.001 ) , a history of preceding Diseasemyelodysplastic syndromes , and with a more immature immunophenotype compared with patients with wild-type ASXL1 ( ASXL1wt ) .
23018865
In multivariable analysis , ASXL1mut was an independent adverse factor for OS ( P = 0.032 , AdverseOutcomerelative risk : 1.70 ) .
23018865
In conclusion , ASXL1mut belong to the most frequent mutations in AdverseOutcomeintermediate risk group AML .
23020132
METHODS : In this open-label study involving 247 patients with Cancermetastatic melanoma and BRAF V600 mutations , we evaluated the pharmacokinetic activity and safety of oral dabrafenib ( 75 or 150 mg twice daily ) and trametinib ( 1 , 1.5 , or 2 mg daily ) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib ( 150 mg ) plus trametinib ( 1 or 2 mg ) or dabrafenib monotherapy .
23020132
The primary end points were the incidence of Cancercutaneous squamous-cell carcinoma , survival free of melanoma progression , and response .
23020132
The primary end points were the incidence of cutaneous squamous-cell carcinoma , survival free of Cancermelanoma progression , and response .
23020132
CancerCutaneous squamous-cell carcinoma was seen in 7 % of patients receiving combination 150/2 and in 19 % receiving monotherapy ( P = 0.09 ) , whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group ( 71 % vs. 26 % ) .
23020162
METHODS : We randomly assigned patients with CancerHER2 positive advanced breast cancer , who had previously been treated with trastuzumab and a taxane , to T-DM1 or lapatinib plus capecitabine .
23020162
The incidences of Diseasethrombocytopenia and increased serum aminotransferase levels were higher with T-DM1 , whereas the incidences of diarrhea , nausea , vomiting , and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine .
23020162
CONCLUSIONS : T-DM1 significantly prolonged progression-free and overall survival with Diseaseless toxicity than lapatinib plus capecitabine in patients with HER2 positive advanced breast cancer previously treated with trastuzumab and a taxane .
23020162
CONCLUSIONS : T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with CancerHER2 positive advanced breast cancer previously treated with trastuzumab and a taxane .
23029227
Somatic mutations of U2AF1 gene have recently been identified in Diseasemyelodysplastic syndrome ( MDS ) and acute myeloid leukemia ( AML ) .
23029227
Somatic mutations of U2AF1 gene have recently been identified in myelodysplastic syndrome ( MDS ) and Canceracute myeloid leukemia ( AML ) .
23031422
The recent findings brought the necessity of testing the mutational status of a series of genes which had been already identified as responsible for Cancermelanomas development and progression , such as BRAF , CKIT and PTEN : the consequent results are , in fact , essential to guide the assessment of the novel treatment protocols based on tailored targeted therapies .
23031422
We present here the case of a 66 year-old male patient , diagnosed with an Canceradvanced melanoma in June 2011 , and treated with Dabrafenib for double mutant metastatic disease .
23031422
We present here the case of a 66 year-old male patient , diagnosed with an advanced melanoma in June 2011 , and treated with Dabrafenib for Diseasedouble mutant metastatic disease .
23031422
The patient was referred to our attention for a Cancerlarge exophytic malignant melanoma on the left shoulder .
23031422
CancerTumor burden was rapidly growing reaching in few months the size of a tennis ball for the tumor mass located in the shoulder .
23031422
Tumor burden was rapidly growing reaching in few months the size of a tennis ball for the Cancertumor mass located in the shoulder .
23031422
Mutational study of the Cancertumor revealed a double BRAF mutation on V-600E and V600M .
23056499
Persistent RET activation is a frequent event in Cancerpapillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( MTC ) .
23056499
Persistent RET activation is a frequent event in papillary thyroid carcinoma ( PTC ) and Cancermedullary thyroid carcinoma ( MTC ) .
23056499
In these Cancercancers , RET activates the ERK and MAPK , the PI3K/AKT/mTOR and the JAK and STAT3 pathways .
23056499
Here , we tested the efficacy of a JAK1/2- inhibitor , AZD1480 , in the in vitro and in vivo growth of Cancerthyroid cancer cell lines expressing oncogenic RET .
23056499
CancerThyroid cancer cell lines harboring RET and PTC1 ( TPC-1 ) , RET M918T ( MZ-CRC1 ) and RET C634W ( TT ) alterations , as well as TPC-1 xenografts , were treated with JAK inhibitor , AZD1480 .
23056499
This inhibitor led to growth inhibition and/or apoptosis of the Cancerthyroid cancer cell lines in vitro , as well as to tumor regression of TPC-1 xenografts , where it efficiently blocked STAT3 activation in tumor and stromal cells .
23056499
This inhibitor led to growth inhibition and/or apoptosis of the thyroid cancer cell lines in vitro , as well as to Cancertumor regression of TPC-1 xenografts , where it efficiently blocked STAT3 activation in tumor and stromal cells .
23056499
This inhibitor led to growth inhibition and/or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC-1 xenografts , where it efficiently blocked STAT3 activation in Cancertumor and stromal cells .
23056499
However , AZD1480 repressed the growth of STAT3- deficient TPC-1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of STAT3 in the Cancertumor cells .
23056499
In conclusion , AZD1480 effectively blocks proliferation and Cancertumor growth of activated RET- thyroid cancer cell lines , likely through direct RET inhibition in cancer cells as well as by modulation of the microenvironment ( e.g. via JAK and phospho-STAT 3 inhibition in endothelial cells ) .
23056499
In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated CancerRET- thyroid cancer cell lines , likely through direct RET inhibition in cancer cells as well as by modulation of the microenvironment ( e.g. via JAK and phospho-STAT 3 inhibition in endothelial cells ) .
23056499
In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated RET- thyroid cancer cell lines , likely through direct RET inhibition in Cancercancer cells as well as by modulation of the microenvironment ( e.g. via JAK and phospho-STAT 3 inhibition in endothelial cells ) .
23056499
Thus , AZD1480 should be considered as a therapeutic agent for the treatment of RET- activated Cancerthyroid cancers .
23060591
The relationship between the clinical efficacy of pemetrexed and the expression of folate enzymes in Cancerlung cancer cells is unknown .
23060591
PATIENTS AND METHODS : Participants ( n = 50 ) were patients with Canceradvanced non small cell lung cancer ( NSCLC ) treated with pemetrexed .
23060591
Samples were obtained by Cancertumor biopsy before treatment .
23060591
We isolated Cancercancer cells from formalin fixed paraffin embedded tissues using laser microdissection , and mRNA levels were analyzed using real-time reverse transcription polymerase chain reaction .
23060591
CONCLUSION : We specifically analyzed TYMS , DHFR , and GARFT mRNA expression levels in Cancerlung cancer cells from biopsy specimens using laser microdissection .
23079656
We show that only combined deletion of p27 ( Kip1 ) and Cancerretinoblastoma tumor suppressor ( Rb ) is sufficient to rescue the development of Ccnd3 (-/-) thymocytes .
23079656
Furthermore , we show that a small molecule targeting the kinase function of cyclin D3 : CDK4/6 inhibits both cell cycle entry in Cancerhuman T cell acute lymphoblastic leukemia ( T-ALL ) and disease progression in animal models of T-ALL .
23079656
Furthermore , we show that a small molecule targeting the kinase function of cyclin D3 : CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia ( T-ALL ) and Diseasedisease progression in animal models of T-ALL .
23079656
These studies identify unique functions for cyclin D3 : CDK4/6 complexes and suggest potential therapeutic protocols for this Cancerdevastating blood tumor .
23086750
NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in Cancerchronic lymphocytic leukemia but to date they have not been validated in a prospective , controlled clinical trial .
23086750
We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 CancerUnited Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 ( UK LRF CCL4 ) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients .
23094721
BACKGROUND : Regular use of aspirin after a diagnosis of Cancercolon cancer has been associated with a superior clinical outcome .
23094721
We hypothesized that the effect of aspirin on survival and prognosis in patients with Cancercancers characterized by mutated PIK3CA ( the phosphatidylinositol-4 ,5-bisphosphonate 3-kinase , catalytic subunit alpha polypeptide gene ) might differ from the effect among those with wild-type PIK3CA cancers .
23094721
We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA ( the phosphatidylinositol-4 ,5-bisphosphonate 3-kinase , catalytic subunit alpha polypeptide gene ) might differ from the effect among those with Cancerwild-type PIK3CA cancers .
23094721
METHODS : We obtained data on 964 patients with rectal or Cancercolon cancer from the Nurses ' Health Study and the Health Professionals Follow-up Study , including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation .
23094721
We examined Cancertumor markers , including PTGS2 , phosphorylated AKT , KRAS , BRAF , microsatellite instability , CpG island methylator phenotype , and methylation of long interspersed nucleotide element 1 .
23094721
RESULTS : Among patients with Cancermutated-PIK3CA colorectal cancers , regular use of aspirin after diagnosis was associated with superior colorectal cancer specific survival ( multivariate hazard ratio for cancer related death , 0.18 ; 95 % confidence interval [ CI ] , 0.06 to 0.61 ; P < 0.001 by the log-rank test ) and overall survival ( multivariate hazard ratio for death from any cause , 0.54 ; 95 % CI , 0.31 to 0.94 ; P = 0.01 by the log-rank test ) .
23094721
RESULTS : Among patients with mutated-PIK3CA colorectal cancers , regular use of aspirin after diagnosis was associated with Cancersuperior colorectal cancer specific survival ( multivariate hazard ratio for cancer related death , 0.18 ; 95 % confidence interval [ CI ] , 0.06 to 0.61 ; P < 0.001 by the log-rank test ) and overall survival ( multivariate hazard ratio for death from any cause , 0.54 ; 95 % CI , 0.31 to 0.94 ; P = 0.01 by the log-rank test ) .
23094721
RESULTS : Among patients with mutated-PIK3CA colorectal cancers , regular use of aspirin after diagnosis was associated with superior colorectal cancer specific survival ( multivariate hazard ratio for Cancercancer related death , 0.18 ; 95 % confidence interval [ CI ] , 0.06 to 0.61 ; P < 0.001 by the log-rank test ) and overall survival ( multivariate hazard ratio for death from any cause , 0.54 ; 95 % CI , 0.31 to 0.94 ; P = 0.01 by the log-rank test ) .
23094721
In contrast , among patients with wild-type PIK3CA , regular use of aspirin after diagnosis was not associated with Cancercolorectal cancer specific survival ( multivariate hazard ratio , 0.96 ; 95 % CI , 0.69 to 1.32 ; P = 0.76 by the log-rank test ; P = 0.009 for interaction between aspirin and PIK3CA variables ) or overall survival ( multivariate hazard ratio , 0.94 ; 95 % CI , 0.75 to 1.17 ; P = 0.96 by the log-rank test ; P = 0.07 for interaction ) .
23094721
CONCLUSIONS : Regular use of aspirin after diagnosis was associated with longer survival among patients with Cancermutated-PIK3CA colorectal cancer , but not among patients with wild-type PIK3CA cancer .
23094721
CONCLUSIONS : Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer , but not among patients with Cancerwild-type PIK3CA cancer .
23094721
The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in Cancercolorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy .
23111194
PURPOSE : CancerNon small cell lung cancer ( NSCLC ) occurs most frequently in individuals older than 60 years of age .
23111194
EXPERIMENTAL DESIGN : The analysis was performed on formalin fixed Cancertumor tissue from 193 surgically treated NSCLC patients ( 127 , older than 60 y ; 66 , 60 y and younger ) .
23171796
BRAF mutations play a well established role in melanomagenesis ; however , without additional genetic alterations , Cancertumor development is restricted by oncogene induced senescence ( OIS ) .
23171796
In a genetically engineered mouse model , Nf1 mutations suppress Braf induced senescence , promote melanocyte hyperproliferation , and enhance Cancermelanoma development .
23171796
As such , Nf1 and CancerBraf-mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen activated protein and extracellular signal regulated kinase kinase and mTOR .
23171796
Importantly , NF1 is mutated or suppressed in Cancerhuman melanomas that harbor concurrent BRAF mutations , NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors , and NF1 is lost in tumors from patients following treatment with these agents .
23171796
Importantly , NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations , NF1 ablation decreases the sensitivity of Cancermelanoma cell lines to BRAF inhibitors , and NF1 is lost in tumors from patients following treatment with these agents .
23171796
Importantly , NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations , NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors , and NF1 is lost in Cancertumors from patients following treatment with these agents .
23171796
Collectively , these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in Cancermelanoma and show that NF1 and neurofibromin inactivation may have an impact on responses to targeted therapies .
23181703
BACKGROUND : CancerLung cancer is the leading cause of cancer related death worldwide .
23181703
BACKGROUND : Lung cancer is the leading cause of Cancercancer related death worldwide .
23181703
Epidermal growth factor receptor ( EGFR ) -- tyrosine kinase inhibitor ( TKI ) is used for the patients with CancerEGFR-mutant lung cancer .
23181703
The echinoderm microtubule associated protein like 4 ( EML4 ) -- Canceranaplastic lymphoma kinase ( ALK ) fusion oncogene represents one of the newest molecular targets in non small cell lung cancer ( NSCLC ) .
23181703
The echinoderm microtubule associated protein like 4 ( EML4 ) -- anaplastic lymphoma kinase ( ALK ) fusion oncogene represents one of the newest molecular targets in Cancernon small cell lung cancer ( NSCLC ) .
23181703
CASE PRESENTATION : We report a 39-year-old patient diagnosed as Canceradenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene .
23181703
We needs further understanding of the Cancerlung cancer molecular biology and the biomarker information .
23182986
PURPOSE : To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 ( FGFR1 ) amplification in patients with surgically Cancerresected squamous cell carcinoma of the lung ( SCCL ) and the association between smoking and FGFR1 amplification .
23182986
PATIENTS AND METHODS : Gene copy number of FGFR1 was investigated in Cancermicroarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available .
23182986
PATIENTS AND METHODS : Gene copy number of FGFR1 was investigated in microarrayed tumors from 262 patients with SCCL who had Cancertumor tissue as well as smoking and survival data available .
23182986
Gene copy number was evaluated by fluorescent in situ hybridization , and an FGFR1 amplified Cancertumor ( FGFR1 amp ( + ) ) was prespecified as a tumor with nine or more copies of FGFR1 .
23182986
Gene copy number was evaluated by fluorescent in situ hybridization , and an FGFR1 amplified tumor ( FGFR1 amp ( + ) ) was prespecified as a Cancertumor with nine or more copies of FGFR1 .
23182986
Multivariate modeling confirmed that patients with FGFR1 amp ( + ) had a significantly greater AdverseOutcomerisk of recurrence and death than those without FGFR1 amp ( + ) after adjusting for sex , smoking status , pathologic stage , and adjuvant chemotherapy ( DFS : adjusted hazard ratio [ AHR ] , 2.24 ; 95 % CI , 1.45 to 3.45 ; P < .001 ; OS : AHR , 1.83 ; 95 % CI , 1.15 to 2.89 ; P = .01 ) .
23188704
The antiapoptotic factor Livin has been considered critical for Cancertumor progression and poor prognosis for variant types of tumors .
23188704
The antiapoptotic factor Livin has been considered critical for tumor progression and AdverseOutcomepoor prognosis for variant types of tumors .
23188704
The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of Cancertumors .
23188704
However , there are only limited reports regarding its expression and biological functions in Cancercolon cancer .
23188704
Here , we examined Livin expression in four Cancercolon cancer cell lines ( HCT116 , RKO , KM12C , and SW620 ) in the presence or absence of cisplatin that was used as a model reagent .
23188704
The stable overexpression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin , while the knockdown of Livin by siRNA rendered Cancercolon cancer cells more sensitive to cisplatin .
23188704
Our study , along with others , highlighted the potential of Livin for Cancercancer therapy in colon cancer .
23188704
Our study , along with others , highlighted the potential of Livin for cancer therapy in Cancercolon cancer .
23190221
BACKGROUND : Resistance to tyrosine kinase inhibitors in patients with Cancerchronic myeloid leukemia ( CML ) and Philadelphia chromosome positive acute lymphoblastic leukemia ( Ph positive ALL ) is frequently caused by mutations in the BCR-ABL kinase domain .
23190221
BACKGROUND : Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia ( CML ) and CancerPhiladelphia chromosome positive acute lymphoblastic leukemia ( Ph positive ALL ) is frequently caused by mutations in the BCR-ABL kinase domain .
23190221
METHODS : In this phase 1 dose escalation study , we enrolled 81 patients with Cancerresistant hematologic cancers , including 60 with CML and 5 with Ph positive ALL .
23190221
RESULTS : Dose limiting toxic effects included elevated lipase or amylase levels and Diseasepancreatitis .
23190221
CONCLUSIONS : Ponatinib was highly active in heavily pretreated patients with CancerPh positive leukemias with resistance to tyrosine kinase inhibitors , including patients with the BCR-ABL T315I mutation , other mutations , or no mutations .
23200175
BACKGROUND : No targeted therapies are available for CancerKRAS-mutant non-small-cell lung cancer ( NSCLC ) .
23200175
Selumetinib is an inhibitor of MEK1 and MEK2 , downstream of KRAS , with preclinical evidence of synergistic activity with docetaxel in CancerKRAS-mutant cancers .
23200175
Of these , one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their Cancertumours were not confirmed to be KRAS mutation positive .
23200175
The most common grade 3-4 adverse events were Diseaseneutropenia ( 29 [ 67 % ] of 43 patients in the selumetinib group vs 23 [ 55 % ] of 42 patients in the placebo group ) , febrile neutropenia ( eight [ 18 % ] of 44 patients in the selumetinib group vs none in the placebo group ) , dyspnoea ( one [ 2 % ] of 44 patients in the selumetinib group vs five [ 12 % ] of 42 in the placebo group ) , and asthenia ( four [ 9 % ] of 44 patients in the selumetinib group vs none in the placebo group ) .
23200175
The most common grade 3-4 adverse events were neutropenia ( 29 [ 67 % ] of 43 patients in the selumetinib group vs 23 [ 55 % ] of 42 patients in the placebo group ) , Diseasefebrile neutropenia ( eight [ 18 % ] of 44 patients in the selumetinib group vs none in the placebo group ) , dyspnoea ( one [ 2 % ] of 44 patients in the selumetinib group vs five [ 12 % ] of 42 in the placebo group ) , and asthenia ( four [ 9 % ] of 44 patients in the selumetinib group vs none in the placebo group ) .
23200175
The most common grade 3-4 adverse events were neutropenia ( 29 [ 67 % ] of 43 patients in the selumetinib group vs 23 [ 55 % ] of 42 patients in the placebo group ) , febrile neutropenia ( eight [ 18 % ] of 44 patients in the selumetinib group vs none in the placebo group ) , dyspnoea ( one [ 2 % ] of 44 patients in the selumetinib group vs five [ 12 % ] of 42 in the placebo group ) , and Diseaseasthenia ( four [ 9 % ] of 44 patients in the selumetinib group vs none in the placebo group ) .
23204226
The antibody trastuzumab is approved for treatment of patients with HER2 ( CancerERBB2 )-overexpressing breast cancer .
23204226
A significant fraction of these Cancertumors are either intrinsically resistant or acquire resistance rendering the drug ineffective .
23204226
Herein , we examined the effects of PI3K blockade in Cancertrastuzumab resistant breast cancer cell lines .
23204226
Compared with XL147 alone , the combination exhibited a superior antitumor effect against Cancertrastuzumab resistant tumor xenografts .
23204226
Furthermore , treatment with XL147 and trastuzumab reduced the Cancercancer stem-cell ( CSC ) fraction within trastuzumab resistant cells both in vitro and in vivo .
23204226
In a cohort of patients with HER2 overexpressing Cancerbreast cancer treated with trastuzumab , higher pretreatment tumor levels of survivin RNA correlated with poor response to therapy .
23204226
In a cohort of patients with HER2 overexpressing breast cancer treated with trastuzumab , Cancerhigher pretreatment tumor levels of survivin RNA correlated with poor response to therapy .
23204226
Together , our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors , CSCs can be reduced within HER2 ( + ) Cancertumors , potentially preventing acquired resistance to anti-HER2 therapy .
23213094
Activating mutations or amplifications in MET have been described in patients with Cancerpapillary renal cell carcinoma ( PRCC ) .
23213094
ORR by Response Evaluation Criteria in CancerSolid Tumors ( RECIST ) 1.0 was 13.5 % , median progression-free survival was 9.3 months , and median overall survival was not reached .
23213094
The most frequent adverse events of any grade associated with foretinib were fatigue , hypertension , Diseasegastrointestinal toxicities , and nonfatal pulmonary emboli .
23213094
CONCLUSION : Foretinib demonstrated activity in patients with advanced PRCC with a Diseasemanageable toxicity profile and a high response rate in patients with germline MET mutations .
23218766
BACKGROUND : Expression of class IotaIotaIota beta-tubulin ( betaIotaIotaIota-tubulin ) correlates with Cancertumor progression and resistance to taxane based therapies for several human malignancies including breast cancer .
23218766
BACKGROUND : Expression of class IotaIotaIota beta-tubulin ( betaIotaIotaIota-tubulin ) correlates with tumor progression and resistance to taxane based therapies for Cancerseveral human malignancies including breast cancer .
23218766
BACKGROUND : Expression of class IotaIotaIota beta-tubulin ( betaIotaIotaIota-tubulin ) correlates with tumor progression and resistance to taxane based therapies for several human malignancies including Cancerbreast cancer .
23218766
However its predictive value in a neoadjuvant setting in Cancerbreast cancer remains unexplored .
23218766
The objective of this explorative study was to determine whether betaIotaIotaIota-tubulin expression in Cancerbreast cancer correlated with pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy .
23218766
PATIENTS AND METHODS : We determined betaIotaIotaIota-tubulin expression in 85 Cancerbreast cancers , including 41 localized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery .
23218766
PATIENTS AND METHODS : We determined betaIotaIotaIota-tubulin expression in 85 breast cancers , including 41 Cancerlocalized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery .
23218766
betaIotaIotaIota-tubulin expression was evaluated by immunohistochemical methods and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using Cancerresidual cancer burden ( RCB ) score .
23218766
RESULTS : High betaIotaIotaIota-tubulin expression was significantly associated with poorly differentiated Cancerhigh-grade breast cancers ( P = .003 ) but not with tumor size , estrogen receptor ( ER ) status , or human epidermal growth factor receptor 2 ( HER2 )/neu overexpression .
23218766
RESULTS : High betaIotaIotaIota-tubulin expression was significantly associated with poorly differentiated high-grade breast cancers ( P = .003 ) but not with Cancertumor size , estrogen receptor ( ER ) status , or human epidermal growth factor receptor 2 ( HER2 )/neu overexpression .
23218766
In CancerER (-) tumors treated with neoadjuvant chemotherapy , high betaIotaIotaIota-tubulin expression was associated with a significantly greater likelihood of achieving a good pathologic response to chemotherapy as reflected by lower RCB scores ( P = .021 ) .
23218766
CONCLUSION : This study reveals differential betaIotaIotaIota-tubulin expression in Cancerbreast cancers of different histologic grades , hormone receptors , and HER2 and neu status .
23218766
It also suggests a potential role for betaIotaIotaIota-tubulin as a predictive biomarker for response in neoadjuvant chemotherapy for ER (-) Cancerbreast cancer , which has not been previously reported .
23220880
Data from 8 Cancerbreast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification .
23220880
Data from 8 breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in Cancercancers lacking HER2 gene amplification .
23220880
These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in Cancerbreast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.SIGNIFICANCE : We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis .
23220880
These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for Cancerbreast cancer treatment.SIGNIFICANCE : We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis .
23220880
These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.SIGNIFICANCE : We show that the majority of HER2 somatic mutations in Cancerbreast cancer patients are activating mutations that likely drive tumorigenesis .
23220880
Our results suggest that patients with CancerHER2 mutation positive breast cancers could benefit from existing HER2 targeted drugs .
23222956
CancerAtypical chronic myeloid leukemia ( aCML ) shares clinical and laboratory features with CML , but it lacks the BCR-ABL1 fusion .
23222956
Targeted resequencing of 70 aCMLs , 574 Cancerdiverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases , including 17 of 70 aCMLs ( 24.3 % ; 95 % confidence interval ( CI ) = 16-35 % ) .
23222956
Targeted resequencing of 70 aCMLs , 574 diverse hematological malignancies and 344 Cancercancer cell lines identified SETBP1 mutations in 24 cases , including 17 of 70 aCMLs ( 24.3 % ; 95 % confidence interval ( CI ) = 16-35 % ) .
23222956
Most mutations ( 92 % ) were located between codons 858 and 871 and were identical to changes seen in individuals with DiseaseSchinzel-Giedion syndrome .
23222956
In summary , mutated SETBP1 represents a newly discovered oncogene present in aCML and closely Diseaserelated diseases .
23231951
PURPOSE : Oncogenic signaling in Cancergastrointestinal stromal tumors ( GIST ) is sustained via PI3K and AKT pathway .
23231951
CancerTumor response was assessed by volume measurements , micro-PET imaging , histopathology , and immunoblotting .
23231951
RESULTS : In all models , GDC-0941 caused Cancertumor growth stabilization , inhibiting tumor cell proliferation , but did not induce apoptosis .
23231951
RESULTS : In all models , GDC-0941 caused tumor growth stabilization , inhibiting Cancertumor cell proliferation , but did not induce apoptosis .
23231951
Under GDC+IMA , Cancerprofound tumor regression , superior to either treatment alone , was observed .
23231951
CancerTumor regrowth assays confirmed superior activity of GDC+IMA over imatinib ; in three of six models , tumor volume remained reduced and stable even after treatment discontinuation .
23231951
Tumor regrowth assays confirmed superior activity of GDC+IMA over imatinib ; in three of six models , Cancertumor volume remained reduced and stable even after treatment discontinuation .
23231951
CONCLUSION : GDC+IMA has significant antitumor efficacy in GIST xenografts , inducing more Cancersubstantial tumor regression , apoptosis , and durable effects than imatinib .
23231951
Notably , after treatment withdrawal , Cancertumor regression was sustained in tumors exposed to GDC+IMA , which was not observed under imatinib .
23231951
Notably , after treatment withdrawal , tumor regression was sustained in Cancertumors exposed to GDC+IMA , which was not observed under imatinib .
23238879
This study aimed to determine whether the expression of Cancervarious tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in metastatic recurrent endometrial cancer .
23238879
This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts Cancertumor response to everolimus in metastatic recurrent endometrial cancer .
23238879
This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in Cancermetastatic recurrent endometrial cancer .
23238879
CancerTumor blocks from 44 patients of a phase II clinical trial receiving everolimus until progression or toxicity were collected and evaluated at 3 and 6 months for response .
23238879
Tumor blocks from 44 patients of a phase II clinical trial receiving everolimus until progression or Diseasetoxicity were collected and evaluated at 3 and 6 months for response .
23238879
Twelve of 34 evaluable patients had partial response or Diseasestable disease ( PR , SD ) and 22 had progressive disease ( PD ) .
23238879
Twelve of 34 evaluable patients had partial response or stable disease ( PR , SD ) and 22 had Diseaseprogressive disease ( PD ) .
23238879
However , Cancerendometrial cancer patients with K-RAS mutations do not seem to derive benefit from everolimus treatment .
23265711
BACKGROUND : The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent and Cancermetastatic squamous cell carcinoma of the head and neck ( SCCHN ) and KRAS wild-type metastatic colorectal cancer ( mCRC ) .
23265711
BACKGROUND : The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent and metastatic squamous cell carcinoma of the head and neck ( SCCHN ) and CancerKRAS wild-type metastatic colorectal cancer ( mCRC ) .
23265711
In Canceradvanced non-small-cell lung cancer ( NSCLC ) , high EGFR expression was identified as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy .
23265711
In advanced non-small-cell lung cancer ( NSCLC ) , high EGFR expression was identified as a Cancertumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy .
23265711
We investigated whether Cancertumour EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL study patients .
23265711
METHODS : Prospectively collected Cancertumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score ( scale 1-300 ) for patients in the EXTREME and CRYSTAL studies .
23265711
For each study , the association between Cancertumour immunohistochemistry score and cetuximab benefit was investigated .
23265711
FINDINGS : CancerTumour EGFR immunohistochemistry data were available for 411 of 442 ( 93 % ) patients from the EXTREME study intention-to-treat ( ITT ) population and 664 of 666 ( 100 % ) patients from the ITT population of the CRYSTAL study with EGFR expressing , KRAS wild-type disease .
23265711
FINDINGS : Tumour EGFR immunohistochemistry data were available for 411 of 442 ( 93 % ) patients from the EXTREME study intention-to-treat ( ITT ) population and 664 of 666 ( 100 % ) patients from the ITT population of the CRYSTAL study with EGFR expressing , DiseaseKRAS wild-type disease .
23265711
INTERPRETATION : The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent and metastatic SCCHN and KRAS wild-type mCRC regardless of Cancertumour EGFR expression level , indicating that in contrast to findings in NSCLC , EGFR expression level is not a clinically useful predictive biomarker in these settings .
23280579
The higher incidence of Cancerbreast cancer in developed countries has been tempered by reductions in mortality , largely attributable to mammographic screening programmes and advances in adjuvant therapy .
23280579
The higher incidence of breast cancer in developed countries has been tempered by reductions in AdverseOutcomemortality , largely attributable to mammographic screening programmes and advances in adjuvant therapy .
23280579
Oestrogen receptor alpha ( ERalpha ) , progesterone receptor ( PgR ) and human epidermal growth factor receptor 2 ( HER2 ) are established biomarkers evaluated at diagnosis , which identify cardinal subtypes of Cancerbreast cancer .
23280579
However , the goals of personalized medicine and targeted therapies demand further information regarding AdverseOutcomeresidual risk and potential benefit of additional treatments in specific circumstances .
23280579
Expanding the utility of biomarkers to lower resource settings requires an emphasis on cost effectiveness , quality assurance and possible international variations in Cancertumor biology ; the potential for improved clinical outcomes should be justified against logistical and economic considerations .
23287563
PURPOSE : We describe the preclinical pharmacology and antitumor activity of GDC-0068 , a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of Cancerhuman cancers .
23287563
EXPERIMENTAL DESIGN : The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway , and response to GDC-0068 was evaluated in Cancerhuman cancer cell lines and xenograft models with various genetic backgrounds , either as a single agent or in combination with chemotherapeutic agents .
23287563
RESULTS : GDC-0068 blocked Akt signaling both in cultured Cancerhuman cancer cell lines and in tumor xenograft models as evidenced by dose dependent decrease in phosphorylation of downstream targets .
23287563
RESULTS : GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in Cancertumor xenograft models as evidenced by dose dependent decrease in phosphorylation of downstream targets .
23287563
Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of Cancercancer cell lines .
23287563
In Cancermultiple tumor xenograft models , oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression .
23287563
In multiple tumor xenograft models , oral administration of GDC-0068 resulted in antitumor activity ranging from Cancertumor growth delay to regression .
23287563
CONCLUSIONS : GDC-0068 is a highly selective , orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in Cancerhuman cancer cells in vitro and in vivo .
23287563
Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in Cancercancers with activated Akt signaling .
23288408
RAF inhibitors such as vemurafenib and dabrafenib block BRAF mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAF ( CancerV600E )-mutant melanoma .
23288408
NF1 mutations were observed in CancerBRAF-mutant tumor cells that are intrinsically resistant to RAF inhibition and in melanoma tumors obtained from patients exhibiting resistance to vemurafenib , thus showing the clinical potential for NF1 driven resistance to RAF and MEK targeted therapies .
23288408
NF1 mutations were observed in BRAF-mutant tumor cells that are intrinsically resistant to RAF inhibition and in Cancermelanoma tumors obtained from patients exhibiting resistance to vemurafenib , thus showing the clinical potential for NF1 driven resistance to RAF and MEK targeted therapies .
23313110
The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs ) in Cancernon small cell lung cancer ( NSCLC ) has not been fully understood .
23313110
KRAS mutations were detected in 69 of 448 patients ( 15.4 % ) , mostly in smokers ( 17.86 % vs. 5.8 % , P = 0.0048 ) , and appeared more frequently in Canceradenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified ( 21 % vs. 6.99 % vs. 4.4 % , P = 0.0004 ) .
23322234
AIB1 ( amplified in Cancerbreast cancer 1 ) is an estrogen receptoralpha ( ERalpha ) co-activator , known to be amplified and overexpressed in a fraction of breast cancers .
23322234
AIB1 ( amplified in breast cancer 1 ) is an estrogen receptoralpha ( ERalpha ) co-activator , known to be amplified and overexpressed in a fraction of Cancerbreast cancers .
23322234
The different functions of AIB1 in ERalpha positive and Disease-negative disease are poorly understood .
23322234
Therefore , we analyzed the clinical significance of AIB1 in Cancerbreast cancer with respect to ERalpha-status and characterized the subgroups .
23322234
2,197 Cancerbreast carcinomas sampled on a pre-existing tissue microarray ( TMA ) were analyzed for AIB1 expression and amplification by immunohistochemistry ( IHC ) and fluorescence in situ hybridization ( FISH ) .
23322234
RESULTS : AIB1 expression was detected in 60 % of the Cancertumors .
23322234
It was associated with Cancertumor size ( p = 0.003 ) , high histological grade ( p < 0.0001 ) , poor disease specific , and overall survival ( p = 0.0018 and p = 0.003 ) .
23322234
It was associated with tumor size ( p = 0.003 ) , high histological grade ( p < 0.0001 ) , Diseasepoor disease specific , and overall survival ( p = 0.0018 and p = 0.003 ) .
23322234
AIB1 amplification was found in 11 % of the Cancercarcinomas .
23322234
It was associated with high histological grade ( p = 0.0012 ) , lymph node involvement ( p = 0.0163 ) , and Diseasepoor disease specific survival ( p = 0.0032 ) but not with overall survival ( p = 0.1672 ) or ER status ( p = 0.4456 ) .
23322234
If CancerER positive tumors were stratified according to their AIB1 amplification status , there was a significant worse disease specific survival in cases showing AIB1 amplification ( p = 0.0017 ) .
23322234
If ER positive tumors were stratified according to their AIB1 amplification status , there was a Diseasesignificant worse disease specific survival in cases showing AIB1 amplification ( p = 0.0017 ) .
23322234
AIB1 expression is associated with unfavorable prognosis and Cancertumor phenotype .
23322234
AIB1 has an impact on cell cycle regulation in ERalpha positive as well as CancerERalpha negative tumors .
23322234
Furthermore , AIB1 amplification characterizes a subgroup of CancerERalpha positive breast cancer with worse outcome .
23322234
Therefore , AIB1 might be helpful to identify those CancerERalpha positive breast cancers patients who are candidates for adjuvant chemotherapy .
23325582
PURPOSE : To investigate whether EGF receptor ( EGFR ) pathway mutations predicted response to monotherapy with panitumumab , an anti-EGFR monoclonal antibody , in a randomized phase III study of Cancermetastatic colorectal cancer .
23329234
BACKGROUND : Standard clinical parameters can not accurately differentiate indolent from Canceraggressive prostate cancer .
23329234
Our previous work showed that immunohistochemical ( IHC ) Ki-67 improved prediction of Cancerprostate cancer death in a cohort of conservatively treated clinically localised prostate cancers diagnosed by transurethral resection of the prostate ( TURP ) .
23329234
Our previous work showed that immunohistochemical ( IHC ) Ki-67 improved prediction of prostate cancer death in a cohort of conservatively treated clinically Cancerlocalised prostate cancers diagnosed by transurethral resection of the prostate ( TURP ) .
23329234
The percentage of Ki-67 positively stained malignant cells per core was measured and the maximum score per individual used in analysis of time to death from Cancerprostate cancer using a Cox proportional hazards model .
23329234
It was less informative than in the previous TURP cohort where Cancertumour samples were larger and more comprehensive , but in more contemporary cohorts with larger numbers of biopsies per patient , Ki-67 may prove a more powerful biomarker .
23333114
BACKGROUND : CancerClear-cell renal-cell carcinomas display divergent clinical behaviours .
23333114
We discovered that BAP1 is mutated in about 15 % of Cancerclear-cell renal-cell carcinoma , and that BAP1 and PBRM1 mutations are largely mutually exclusive .
23333114
The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients with BAP1-mutant and CancerPBRM1-mutant tumours had different overall survival .
23333114
METHODS : In this retrospective analysis , we assessed 145 patients with Cancerprimary clear-cell renal-cell carcinoma and defined PBRM1 and BAP1 mutation status from the University of Texas Southwestern Medical Center ( UTSW ) , TX , USA , between 1998 and 2011 .
23333114
We classified patients into those with CancerBAP1-mutant tumours and those with tumours exclusively mutated for PBRM1 ( PBRM1-mutant ) .
23333114
We classified patients into those with BAP1-mutant tumours and those with Cancertumours exclusively mutated for PBRM1 ( PBRM1-mutant ) .
23333114
We used a second independent cohort ( n = 327 ) from The CancerCancer Genome Atlas ( TCGA ) for validation .
23333114
In both cohorts , more than 80 % of patients had localised or Diseaselocoregional disease at presentation .
23333114
Overall both cohorts were similar , although the TCGA had more patients with metastatic and Diseasehigher-grade disease , and more TCGA patients presented before molecularly targeted therapies became available .
23333114
FINDINGS : The median overall survival in the UTSW cohort was significantly shorter for patients with CancerBAP1-mutant tumours ( 4.6 years ; 95 % CI 2.1-7 .2 ) , than for patients with PBRM1-mutant tumours ( 10.6 years ; 9.8-11 .5 ) , corresponding to a HR of 2.7 ( 95 % CI 0.99-7 .6 , p = 0.044 ) .
23333114
FINDINGS : The median overall survival in the UTSW cohort was significantly shorter for patients with BAP1-mutant tumours ( 4.6 years ; 95 % CI 2.1-7 .2 ) , than for patients with CancerPBRM1-mutant tumours ( 10.6 years ; 9.8-11 .5 ) , corresponding to a HR of 2.7 ( 95 % CI 0.99-7 .6 , p = 0.044 ) .
23333114
Median overall survival in the TCGA cohort was 1.9 years ( 95 % CI 0.6-3 .3 ) for patients with CancerBAP1-mutant tumours and 5.4 years ( 4.0-6 .8 ) for those with PBRM1-mutant tumours .
23333114
Median overall survival in the TCGA cohort was 1.9 years ( 95 % CI 0.6-3 .3 ) for patients with BAP1-mutant tumours and 5.4 years ( 4.0-6 .8 ) for those with CancerPBRM1-mutant tumours .
23333114
INTERPRETATION : Our findings identify mutation defined subtypes of Cancerclear-cell renal-cell carcinoma with distinct clinical outcomes , a high-risk BAP1-mutant group and a favourable PBRM1-mutant group .
23333114
These data establish the basis for a molecular genetic classification of Cancerclear-cell renal-cell carcinoma that could influence treatment decisions in the future .
23340172
We studied the effect of everolimus , an inhibitor of the mammalian target of rapamycin ( mTOR ) on Cancerhuman gastric cancer cell lines .
23340172
In conclusion , phosphorylation of 4E-BP1 may be a predictive biomarker of everolimus sensitivity in Cancergastric cancer .
23341344
CancerT-cell acute lymphoblastic leukemia ( T-ALL ) is an aggressive and heterogeneous disease .
23341344
T-cell acute lymphoblastic leukemia ( T-ALL ) is an aggressive and Diseaseheterogeneous disease .
23341344
In conclusion , RUNX1 and DNMT3A are frequently mutated in T-ALL and are associated with AdverseOutcomepoor prognosis in early T-ALL .
23344087
BACKGROUND : CancerAnaplastic lymphoma kinase ( ALK )-rearranged non-small-cell lung cancer ( NSCLC ) is markedly sensitive to the ALK inhibitor crizotinib .
23344087
BACKGROUND : Anaplastic lymphoma kinase ( CancerALK )-rearranged non-small-cell lung cancer ( NSCLC ) is markedly sensitive to the ALK inhibitor crizotinib .
23344087
METHODS : CancerTumor samples were derived from seven ALK positive NSCLC patients who showed acquired resistance to crizotinib , and these patients were analyzed for ALK , EGFR , and KRAS mutations and ALK and EGFR gene amplifications .
23346317
The standard treatment of Canceradvanced ovarian cancer is rapidly changing .
23346317
As we begin to understand that Cancerepithelial ovarian cancer is a heterogeneous disease , our treatment strategies are evolving to include novel biologic drugs that specifically exploit altered pathways .
23346317
As we begin to understand that epithelial ovarian cancer is a Diseaseheterogeneous disease , our treatment strategies are evolving to include novel biologic drugs that specifically exploit altered pathways .
23346317
Surgery remains an essential component in the treatment of Cancerovarian cancer ; however , the importance of surgical specialization and defining " optimal cytoreduction " as no visible residual disease has been further validated .
23346317
Surgery remains an essential component in the treatment of ovarian cancer ; however , the importance of surgical specialization and defining " optimal cytoreduction " as no Diseasevisible residual disease has been further validated .
23346317
Ongoing studies are defining the role of neoadjuvant chemotherapy in the upfront treatment of Canceradvanced ovarian cancer .
23348520
BACKGROUND : In Cancermetastatic colorectal cancer ( mCRC ) , KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor ( EGFR )-targeted therapies .
23348520
To identify additional predictive markers , we investigated the importance of HER2 , the primary EGFR dimerisation partner , in this Diseaseparticular disease .
23374602
BACKGROUND : More than half of patients with KRAS-wild type advanced Cancercolorectal cancer ( CRC ) fail anti-EGFR monoclonal antibodies .
23374602
METHODS : Previously genotyped ( KRAS , NRAS , BRAF , PIK3CA mutations ) formalin fixed Cancerparaffin embedded tumour biopsies of 226 cetuximab treated CRC patients ( 1st to 3rd line therapy ) were assessed for mRNA expression of epidermal growth factor receptor ( EGFR ) and its ligands EGF , Transofrming Growth Factor-a ( TGFA ) , Amphiregulin ( AREG ) and Epiregulin ( EREG ) with real time quantitative PCR .
23374602
Mutations were detected in 72 ( 31.9 % ) Cancertumours for KRAS , in 6 ( 2.65 % ) for BRAF , in 7 ( 3.1 % ) for NRAS and in 37 ( 16.4 % ) for PIK3CA .
23374602
In multivariate analysis , favourable predictive factors were high AREG mRNA in CancerKRAS wild type tumours , high EREG mRNA , low Ephrin A2 receptor mRNA .
23374602
AREG mRNA reflects EGFR signalling in CancerKRAS wild type tumours , predicting for cetuximab efficacy when high and failure when low .
23377281
CancerAcute lymphoblastic leukemia ( ALL ) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors .
23377281
Acute lymphoblastic leukemia ( ALL ) is an Canceraggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors .
23377281
Despite intensive chemotherapy , 20 % of pediatric patients and over 50 % of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy , making Diseasedisease relapse and resistance to therapy the most substantial challenge in the treatment of this disease .
23377281
Despite intensive chemotherapy , 20 % of pediatric patients and over 50 % of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy , making disease relapse and resistance to therapy the most substantial challenge in the treatment of this Diseasedisease .
23377281
These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in Diseasedisease progression and chemotherapy resistance in ALL .
23382472
PURPOSE : Trastuzumab emtansine ( T-DM1 ) , an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker , has shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 ( HER2 ) Cancer-positive metastatic breast cancer ( MBC ) whose disease had progressed on HER2 targeted therapy in the metastatic setting .
23382472
PURPOSE : Trastuzumab emtansine ( T-DM1 ) , an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker , has shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 ( HER2 ) -positive metastatic breast cancer ( MBC ) whose Diseasedisease had progressed on HER2 targeted therapy in the metastatic setting .
23382472
PATIENTS AND METHODS : Patients ( N = 137 ) with HER2 positive MBC or recurrent locally Canceradvanced breast cancer were randomly assigned to trastuzumab plus docetaxel ( HT ; n = 70 ) or T-DM1 ( n = 67 ) as first-line treatment until disease progression or unacceptable toxicity .
23382472
PATIENTS AND METHODS : Patients ( N = 137 ) with HER2 positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel ( HT ; n = 70 ) or T-DM1 ( n = 67 ) as first-line treatment until Diseasedisease progression or unacceptable toxicity .
23382472
PATIENTS AND METHODS : Patients ( N = 137 ) with HER2 positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel ( HT ; n = 70 ) or T-DM1 ( n = 67 ) as first-line treatment until disease progression or Diseaseunacceptable toxicity .
23390248
Although standard chemotherapies are commonly used to treat most types of Cancersolid tumors , such treatment often results in inadequate response to , or relapse after , therapy .
23390248
This is particularly relevant for Cancerlung cancer because most patients are diagnosed with advanced-stage disease and are treated with frontline chemotherapy .
23390248
This is particularly relevant for lung cancer because most patients are diagnosed with Diseaseadvanced-stage disease and are treated with frontline chemotherapy .
23390248
By studying the Cancerresidual tumor cells that remain after chemotherapy in several in vivo non small cell lung cancer models , we found that these cells have increased levels of human epidermal growth factor receptor ( HER ) signaling due , in part , to the enrichment of a preexisting NRG1 ( HI ) subpopulation .
23390248
By studying the residual tumor cells that remain after chemotherapy in several in vivo Cancernon small cell lung cancer models , we found that these cells have increased levels of human epidermal growth factor receptor ( HER ) signaling due , in part , to the enrichment of a preexisting NRG1 ( HI ) subpopulation .
23390248
Inhibition of NRG1 signaling inhibits Cancerprimary tumor growth and enhances the magnitude and duration of the response to chemotherapy .
23390248
Moreover , we show that inhibition of ligand mediated Her4 signaling impedes Diseasedisease relapse in cases where NRG1 inhibition is insufficient .
23390248
These findings demonstrate that ligand dependent Her4 signaling plays an important role in Diseasedisease relapse .
23414587
BACKGROUND : Patients with Cancermelanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors .
23414587
However , no targeted treatments exist for patients with CancerBRAF wild-type tumours , including those with NRAS mutations .
23414587
We aimed to assess the use of MEK162 , a small-molecule MEK1/2 inhibitor , in patients with NRAS mutated or Val600 BRAF mutated Canceradvanced melanoma .
23414587
METHODS : In our open-label , non randomised , phase 2 study , we assigned patients with NRAS mutated or BRAF mutated Canceradvanced melanoma to one of three treatment arms on the basis of mutation status .
23414587
Patients were enrolled at university hospitals or Cancerprivate cancer centres in Europe and the USA .
23414587
The three arms were : twice-daily MEK162 45 mg for NRAS mutated Cancermelanoma , twice-daily MEK162 45 mg for BRAF mutated melanoma , and twice-daily MEK162 60 mg for BRAF mutated melanoma .
23414587
The three arms were : twice-daily MEK162 45 mg for NRAS mutated melanoma , twice-daily MEK162 45 mg for BRAF mutated Cancermelanoma , and twice-daily MEK162 60 mg for BRAF mutated melanoma .
23414587
The three arms were : twice-daily MEK162 45 mg for NRAS mutated melanoma , twice-daily MEK162 45 mg for BRAF mutated melanoma , and twice-daily MEK162 60 mg for BRAF mutated Cancermelanoma .
23414587
Six ( 20 % ) of 30 patients with NRAS mutated Cancermelanoma had a partial response ( three confirmed ) as did eight ( 20 % ) of 41 patients with BRAF mutated melanoma ( two confirmed ) .
23414587
Six ( 20 % ) of 30 patients with NRAS mutated melanoma had a partial response ( three confirmed ) as did eight ( 20 % ) of 41 patients with BRAF mutated Cancermelanoma ( two confirmed ) .
23414587
The most frequent adverse events were Diseaseacneiform dermatitis ( 18 [ 60 % ] patients with NRAS -mutated melanoma and 15 [ 37 % ] patients with the BRAF mutated melanoma ) , rash ( six [ 20 % ] and 16 [ 39 % ] ) , peripheral oedema ( ten [ 33 % ] and 14 [ 34 % ] ) , facial oedema ( nine [ 30 % ] and seven [ 17 % ] ) , diarrhoea ( eight [ 27 % ] and 15 [ 37 % ] ) , and creatine phosphokinase increases ( 11 [ 37 % ] and nine [ 22 % ] ) .
23414587
The most frequent adverse events were acneiform dermatitis ( 18 [ 60 % ] patients with CancerNRAS -mutated melanoma and 15 [ 37 % ] patients with the BRAF mutated melanoma ) , rash ( six [ 20 % ] and 16 [ 39 % ] ) , peripheral oedema ( ten [ 33 % ] and 14 [ 34 % ] ) , facial oedema ( nine [ 30 % ] and seven [ 17 % ] ) , diarrhoea ( eight [ 27 % ] and 15 [ 37 % ] ) , and creatine phosphokinase increases ( 11 [ 37 % ] and nine [ 22 % ] ) .
23414587
The most frequent adverse events were acneiform dermatitis ( 18 [ 60 % ] patients with NRAS -mutated melanoma and 15 [ 37 % ] patients with the BRAF mutated Cancermelanoma ) , rash ( six [ 20 % ] and 16 [ 39 % ] ) , peripheral oedema ( ten [ 33 % ] and 14 [ 34 % ] ) , facial oedema ( nine [ 30 % ] and seven [ 17 % ] ) , diarrhoea ( eight [ 27 % ] and 15 [ 37 % ] ) , and creatine phosphokinase increases ( 11 [ 37 % ] and nine [ 22 % ] ) .
23414587
Four patients had serious adverse events ( two per arm ) , which included diarrhoea , dehydration , Diseaseacneiform dermatitis , general physical deterioration , irregular heart rate , malaise , and small intestinal perforation .
23414587
INTERPRETATION : To our knowledge , MEK162 is the first targeted therapy to show activity in patients with CancerNRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments .
23414587
INTERPRETATION : To our knowledge , MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a Cancercancer with few effective treatments .
23430109
Ponatinib ( AP24534 ) is a multikinase inhibitor with in vitro and clinical activity in tyrosine kinase inhibitor ( CancerTKI )-resistant chronic myeloid leukemia , irrespective of BCR-ABL KD mutation .
23430109
Ponatinib has demonstrated early clinical efficacy in Cancerchemotherapy resistant acute myeloid leukemia ( AML ) patients with internal tandem duplication ( ITD ) mutations in FLT3 .
23431193
Activating mutations in the Cancerneuroblastoma rat sarcoma viral oncogene homolog ( NRAS ) gene are common genetic events in malignant melanoma being found in 15-25 % of cases .
23431193
Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog ( NRAS ) gene are common genetic events in Cancermalignant melanoma being found in 15-25 % of cases .
23431193
NRAS is thought to activate both mitogen activated protein kinase ( MAPK ) and PI3K signaling in Cancermelanoma cells .
23431193
We studied the influence of different components on the MAP and extracellular signal regulated ( ERK ) kinase ( MEK ) and PI3K and mammalian target of rapamycin ( mTOR )-signaling cascade in CancerNRAS mutant melanoma cells .
23431193
Combined targeting of MEK and PI3K was superior to MEK and mTOR1 ,2 inhibition in all CancerNRAS mutant melanoma cell lines tested , suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited .
23431193
Combined targeting of MEK and PI3K was superior to MEK and mTOR1 ,2 inhibition in all NRAS mutant melanoma cell lines tested , suggesting that PI3K signaling is more important for cell survival in CancerNRAS mutant melanoma when MEK is inhibited .
23431193
However , targeting of PI3K and mTOR1 ,2 in combination with MEK inhibitors is necessary to effectively abolish growth of CancerNRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma .
23431193
However , targeting of PI3K and mTOR1 ,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress Cancerxenografted NRAS mutant melanoma .
23431193
Expression analysis confirms that combined MEK and PI3K and mTOR1 ,2 inhibition predominantly influences genes in the Cancerrat sarcoma ( RAS ) pathway and growth factor receptor pathways , which signal through MEK and ERK and PI3K and mTOR , respectively .
23431193
Our results suggest that combined targeting of the MEK and ERK and PI3K and mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of CancerNRAS mutant melanoma , for which there are currently no effective therapies .
23434733
PURPOSE : To evaluate the safety , pharmacokinetics , and pharmacodynamics of BAY 86-9766 , a selective , potent , orally available , small-molecule allosteric inhibitor of mitogen activated protein kinase 1/2 in patients with Canceradvanced solid tumors .
23434733
CancerTumor specimens were evaluated for mutations in select genes .
23434733
The most Diseasecommon treatment related toxicities were acneiform rash and gastrointestinal toxicity .
23434733
The most common treatment related toxicities were acneiform rash and Diseasegastrointestinal toxicity .
23434733
Of 53 evaluable patients , one patient with Cancercolorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses .
23434733
Of 53 evaluable patients , one patient with colorectal cancer achieved a partial response and 11 patients had Diseasestable disease for 4 or more courses .
23434733
An Cancerocular melanoma specimen harbored a GNAQ activating mutation and exhibited reduced ERK phosphorylation in response to therapy .
23434733
CONCLUSION : This phase I study showed that BAY 86-9766 was well tolerated , with good oral absorption , dose proportional pharmacokinetics , target inhibition at the MTD , and some evidence of clinical benefit across a range of Cancertumor types .
23435671
BACKGROUND : It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in Canceradvanced pancreatic cancer ( PC ) .
23435830
PURPOSE : PIK3CA mutation appears to predict a lack of response to anti-EGFR monoclonal antibody ( mAb ) treatment in patients with Cancermetastatic colorectal cancer ( mCRC ) .
23456958
Adjuvant fluoropyrimidine based ( 5-FU ) chemotherapy is a mainstay of treatment for Cancercolorectal cancer ( CRC ) , but only provides benefit for a subset of patients .
23456958
GRP78 expression was significantly elevated in Cancercancer tissue ( p < 0.0001 ) , and correlated with depth of invasion ( p = 0.029 ) and stage ( p = 0.032 ) .
23456958
Patients with stage II Cancercancers treated by surgery alone , with high GRP78 also had improved survival ( 71 % v 50 % ; p = 0.032 ) .
23456958
GRP78 expression may provide a simple AdverseOutcomeadditional risk stratification to inform the adjuvant treatment of CRC and future studies should combine analysis with determination of p53 status .
23463675
We report the evaluation of correlations among different types of BRAF somatic mutations in Cancermelanoma and their management with BRAF inhibitors .
23463675
21 patients with BRAF mutated Cancermetastatic melanoma were enrolled in the protocol with BRAF inhibitors for compassionate use at the University of Modena .
23463675
V600R mutation and double ( V600E -V600M ) mutation were identified in two Cancermelanomas .
23463675
However , all of them are still under treatment and Diseasedisease progression free .
23470965
PURPOSE : All patients with EGF receptor ( CancerEGFR )-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors ( TKI ) .
23470965
EXPERIMENTAL DESIGN : Patients with Cancerlung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance .
23470965
RESULTS : CancerAdequate tumor samples for molecular analysis were obtained in 155 patients .
23506848
De novo lipogenesis is activated in Cancermost cancers .
23506848
Inhibition of ATP citrate lyase ( ACLY ) , the enzyme that catalyzes the first step of de novo lipogenesis , leads to growth suppression and apoptosis in a subset of Cancerhuman cancer cells .
23506848
Analysis of Cancervarious cancer cell lines revealed that cancer cells with a higher susceptibility to ACLY depletion have lower levels of basal ROS and p-AMPK .
23506848
Analysis of various cancer cell lines revealed that Cancercancer cells with a higher susceptibility to ACLY depletion have lower levels of basal ROS and p-AMPK .
23506848
Finally , p-AMPK levels were significantly correlated to the levels of oxidative DNA damage in Cancercolon cancer tissues , suggesting that p-AMPK reflects cellular ROS levels invitro and invivo .
23515407
PURPOSE : We sought to determine the frequency and clinical characteristics of patients with Cancerlung cancer harboring NRAS mutations .
23515407
We used preclinical models to identify targeted therapies likely to be of benefit against CancerNRAS-mutant lung cancer cells .
23515407
EXPERIMENTAL DESIGN : We reviewed clinical data from patients whose Cancerlung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer ( COSMIC ) to harbor NRAS mutations .
23515407
EXPERIMENTAL DESIGN : We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in CancerCancer ( COSMIC ) to harbor NRAS mutations .
23515407
RESULTS : Among 4,562 patients with Cancerlung cancers tested , NRAS mutations were present in 30 ( 0.7 % ; 95 % confidence interval , 0.45 % -0.94 % ) ; 28 of these had no other driver mutations .
23515407
83 % had Canceradenocarcinoma histology with no significant differences in gender .
23515407
While 95 % of patients were former or current smokers , smoking related G : C > T : A transversions were significantly less frequent in NRAS mutated Cancerlung tumors than KRAS-mutant non small cell lung cancer [ NSCLC ; NRAS : 13 % ( 4/30 ) , KRAS : 66 % ( 1772/2733 ) , P < 0.00000001 ] .
23515407
While 95 % of patients were former or current smokers , smoking related G : C > T : A transversions were significantly less frequent in NRAS mutated lung tumors than CancerKRAS-mutant non small cell lung cancer [ NSCLC ; NRAS : 13 % ( 4/30 ) , KRAS : 66 % ( 1772/2733 ) , P < 0.00000001 ] .
23515407
CONCLUSION : NRAS mutations define a distinct subset of Cancerlung cancers ( ~ 1 % ) with potential sensitivity to MEK inhibitors .
23515910
BACKGROUND : The value of p53 status for predicting response to chemotherapy based treatment in patients with Canceresophageal cancer has been controversial .
23515910
Subgroup analyses based on the treatment and histopathology were performed to explore the usefulness of p53 status for predicting response to therapy in Canceresophageal cancer .
23515910
Wild-type form of p53 status ( low expression of p53 protein and/or wild-type p53 gene ) was associated with high response to chemotherapy based treatment in Canceresophageal cancer ( total major response [ MR ] : risk ratio [ RR ] = 1.09 , 95 % CI = 1.03-1 .16 , P = .003 ; pathological MR : RR = 1.15 , 95 % CI = 1.06-1 .25 , P = .001 ; total complete response [ CR ] : RR = 1.08 , 95 % CI = 1.00-1 .17 , P = .040 ) .
23515910
Wild-type form of p53 status ( low expression of p53 protein and/or wild-type p53 gene ) was associated with high response to chemotherapy based treatment in esophageal cancer ( total major response [ MR ] : AdverseOutcomerisk ratio [ RR ] = 1.09 , 95 % CI = 1.03-1 .16 , P = .003 ; pathological MR : RR = 1.15 , 95 % CI = 1.06-1 .25 , P = .001 ; total complete response [ CR ] : RR = 1.08 , 95 % CI = 1.00-1 .17 , P = .040 ) .
23515910
The similar correlation between the wild-type form p53 and response to therapy were also detected in subgroup analyses ( total MR , pathological MR , and total CR in chemoradiotherapy subgroup ; total MR in chemotherapy subgroup ; total MR and pathological CR in Canceresophageal squamous cell carcinoma [ ESCC ] ) .
23515910
CONCLUSIONS : The current meta-analysis suggested that p53 status might be a predictive biomarker for response to chemotherapy based treatment in Canceresophageal cancer .
23539443
CancerMost colorectal cancers ( CRC ) are initiated by mutations of APC , leading to increased beta-catenin-mediated signaling .
23539443
However , continued requirement of Wnt and beta-catenin signaling for Cancertumor progression in the context of acquired KRAS and other mutations is less well established .
23539443
To attenuate Wnt and beta-catenin signaling in Cancertumors , we have developed potent and specific small-molecule tankyrase inhibitors , G007-LK and G244-LM , that reduce Wnt and beta-catenin signaling by preventing poly ( ADP-ribosyl ) ation dependent AXIN degradation , thereby promoting beta-catenin destabilization .
23539443
It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to Cancerimpact tumor growth in the absence of normal APC activity .
23539443
Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo Cancertumor growth in a subset of APC-mutant CRC xenograft models .
23539443
The full potential of the antitumor activity of G007-LK may be limited by Diseaseintestinal toxicity associated with inhibition of Wnt and beta-catenin signaling and cell proliferation in intestinal crypts .
23549875
PURPOSE : BRAF ( V600E ) mutations are associated with poor clinical prognosis in Cancercolorectal cancer ( CRC ) .
23549875
Although selective BRAF inhibitors are effective for treatment of Cancermelanoma , comparable efforts in CRC have been disappointing .
23549875
Our BRAF ( V600E ) GEMM presented with Cancersessile serrated adenomas and polyps , as seen in humans .
23549875
Combination treatment in vivo resulted in induction of apoptosis and Cancertumor regression .
23558169
The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of Cancercancer cells for cancer therapy .
23558169
The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for Cancercancer therapy .
23558169
One potential drug target is isocitrate dehydrogenase 1 ( IDH1 ) , which is mutated in Cancermultiple human cancers .
23558169
Blockade of mIDH1 impaired the growth of IDH1-mutant -- but not IDH1-wild-type -- Cancerglioma cells without appreciable changes in genome-wide DNA methylation .
23558169
These data suggest that mIDH1 may promote Cancerglioma growth through mechanisms beyond its well characterized epigenetic effects .
23558953
Through a prospective clinical sequencing program for Canceradvanced cancers , four index cases were identified which harbor gene rearrangements of FGFR2 , including patients with cholangiocarcinoma , breast cancer , and prostate cancer .
23558953
Through a prospective clinical sequencing program for advanced cancers , four index cases were identified which harbor gene rearrangements of FGFR2 , including patients with Cancercholangiocarcinoma , breast cancer , and prostate cancer .
23558953
Through a prospective clinical sequencing program for advanced cancers , four index cases were identified which harbor gene rearrangements of FGFR2 , including patients with cholangiocarcinoma , Cancerbreast cancer , and prostate cancer .
23558953
Through a prospective clinical sequencing program for advanced cancers , four index cases were identified which harbor gene rearrangements of FGFR2 , including patients with cholangiocarcinoma , breast cancer , and Cancerprostate cancer .
23558953
After extending our assessment of FGFR rearrangements across Cancermultiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer , bladder cancer , thyroid cancer , oral cancer , glioblastoma , and head and neck squamous cell cancer .
23558953
After extending our assessment of FGFR rearrangements across multiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in Cancerlung squamous cell cancer , bladder cancer , thyroid cancer , oral cancer , glioblastoma , and head and neck squamous cell cancer .
23558953
After extending our assessment of FGFR rearrangements across multiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer , Cancerbladder cancer , thyroid cancer , oral cancer , glioblastoma , and head and neck squamous cell cancer .
23558953
After extending our assessment of FGFR rearrangements across multiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer , bladder cancer , Cancerthyroid cancer , oral cancer , glioblastoma , and head and neck squamous cell cancer .
23558953
After extending our assessment of FGFR rearrangements across multiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer , bladder cancer , thyroid cancer , Canceroral cancer , glioblastoma , and head and neck squamous cell cancer .
23558953
After extending our assessment of FGFR rearrangements across multiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer , bladder cancer , thyroid cancer , oral cancer , Cancerglioblastoma , and head and neck squamous cell cancer .
23558953
After extending our assessment of FGFR rearrangements across multiple tumor cohorts , we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer , bladder cancer , thyroid cancer , oral cancer , glioblastoma , and head and Cancerneck squamous cell cancer .
23558953
Two Cancerbladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo .
23558953
Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners , clinical sequencing efforts , which incorporate transcriptome analysis for gene fusions , are poised to identify rare , targetable FGFR fusions across Cancerdiverse cancer types .
23559153
BACKGROUND : To report on a prospective , investigator driven , phase II study on lapatinib in epidermal growth factor receptor ( CancerEGFR )-positive advanced chordoma patients .
23559153
PATIENTS AND METHODS : From December 2009 to January 2012 , 18 advanced progressing Cancerchordoma patients entered this study ( median age : 61 years ; disease extent : metastatic 72 % and locally advanced 28 % ) .
23559153
PATIENTS AND METHODS : From December 2009 to January 2012 , 18 advanced progressing chordoma patients entered this study ( median age : 61 years ; Diseasedisease extent : metastatic 72 % and locally advanced 28 % ) .
23559153
Patients received lapatinib 1500 mg/day ( mean dose intensity = 1282 mg/day ) , until progression or Diseasetoxicity .
23559153
Secondary end points were RR by Response Evaluation Criteria in CancerSolid Tumor ( RECIST ) , overall survival , progression-free survival ( PFS ) and clinical benefit rate ( CBR ; RECIST complete response + partial response ( PR ) + stable disease ( SD ) > = 6 months ) .
23559153
Secondary end points were RR by Response Evaluation Criteria in Solid Tumor ( RECIST ) , overall survival , progression-free survival ( PFS ) and clinical benefit rate ( CBR ; RECIST complete response + partial response ( PR ) + Diseasestable disease ( SD ) > = 6 months ) .
23559153
CONCLUSIONS : This phase II study showed a modest antitumor activity of lapatinib in Cancerchordoma .
23559153
The clinical exploitation of EGFR targeting in Cancerchordoma needs to be further investigated , both clinically and preclinically .
23565280
KRAS mutations are major factors involved in initiation and maintenance of Cancerpancreatic tumors .
23565280
We screened Cancertumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes .
23565280
We screened tumors from 171 Cancerpancreatic cancer patients for mutations in KRAS and CDKN2A genes .
23565280
Mutations in KRAS were detected in 134 Cancertumors , with 131 in codon 12 and only 3 in codon 61 .
23565280
Deletions and mutations in CDKN2A were detected in 43 Cancertumors .
23565280
Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and Cancerductal adenocarcinomas ( PDAC ) .
23565280
Although , the association of survival in PDAC patients with CDKN2A aberrations in Cancertumors was not statistically significant , the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation ( log-rank-test P = 0.02 ) and a corresponding HR of 3.07 ( 95 % CI 1.33-7 .10 ) .
23565280
Although , the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant , the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in Cancertumors were associated with a median survival of 13.5 months compared to 22 months without mutation ( log-rank-test P = 0.02 ) and a corresponding HR of 3.07 ( 95 % CI 1.33-7 .10 ) .
23568491
Next generation sequencing studies have identified mutations in SF3B1 in Cancerchronic lymphocytic leukemia ( CLL ) at high frequency .
23568491
In CLL , SF3B1 mutation is associated with more Diseaseaggressive disease and shorter survival , and recent studies suggest that it can be incorporated into prognostic schema to improve the prediction of disease progression .
23568491
In CLL , SF3B1 mutation is associated with more aggressive disease and shorter survival , and recent studies suggest that it can be incorporated into prognostic schema to improve the prediction of Diseasedisease progression .
23569304
PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF ( CancerV600 )-mutant melanoma , leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy .
23569304
PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF ( V600 )-mutant melanoma , leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of Cancermetastatic melanoma therapy .
23569304
Baseline mutations in MEK1 ( P124 ) coexisting with BRAF ( V600 ) were noted in seven of 92 samples ; their presence did not preclude Cancerobjective tumor responses .
23569304
These two activating MEK1 mutations had not previously been observed in vivo in biopsies of Cancerprogressive melanoma tumors .
23569304
CONCLUSION Vemurafenib inhibits Cancertumor proliferation and oncogenic BRAF signaling through the MAPK pathway .
23569312
PURPOSE : CDK4 is amplified in > 90 % of well differentiated ( WDLS ) and Cancerdedifferentiated liposarcomas ( DDLS ) .
23569312
In a phase I trial of PD0332991 , several patients with WDLS or DDLS experienced Diseaseprolonged stable disease .
23569312
PATIENTS AND METHODS : Patients age > = 18 years experiencing Diseasedisease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles .
23569312
All were required to have CDK4 amplification by fluorescence in situ hybridization and Cancerretinoblastoma protein ( RB ) expression by immunohistochemistry ( > = 1+ ) .
23569312
Grade 3 to 4 events included Diseaseanemia ( 17 % ) , thrombocytopenia ( 30 % ) , neutropenia ( 50 % ) , and febrile neutropenia ( 3 % ) .
23569312
Grade 3 to 4 events included anemia ( 17 % ) , Diseasethrombocytopenia ( 30 % ) , neutropenia ( 50 % ) , and febrile neutropenia ( 3 % ) .
23569312
Grade 3 to 4 events included anemia ( 17 % ) , thrombocytopenia ( 30 % ) , Diseaseneutropenia ( 50 % ) , and febrile neutropenia ( 3 % ) .
23569312
Grade 3 to 4 events included anemia ( 17 % ) , thrombocytopenia ( 30 % ) , neutropenia ( 50 % ) , and Diseasefebrile neutropenia ( 3 % ) .
23569312
CONCLUSION : Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4 amplified and RB expressing WDLS and DDLS who had Diseaseprogressive disease despite systemic therapy .
23569316
PURPOSE : To analyze the baseline clinicopathologic characteristics of Cancerprostate tumors with germline BRCA1 and BRCA2 ( BRCA1/2 ) mutations and the prognostic value of those mutations on prostate cancer ( PCa ) outcomes .
23569316
PURPOSE : To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 ( BRCA1/2 ) mutations and the prognostic value of those mutations on Cancerprostate cancer ( PCa ) outcomes .
23569316
PATIENTS AND METHODS : This study analyzed the Cancertumor features and outcomes of 2,019 patients with PCa ( 18 BRCA1 carriers , 61 BRCA2 carriers , and 1,940 noncarriers ) .
23569316
The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival ( OS ) , cause specific OS ( CSS ) , CSS in localized PCa ( CSS_M0 ) , metastasis-free survival ( MFS ) , and CSS from Cancermetastasis ( CSS_M1 ) .
23569316
Subgroup analyses confirmed the AdverseOutcomepoor outcomes in BRCA2 patients , whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup .
23569316
CONCLUSION : Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and Cancerdistant metastasis .
23579861
The anti-VEGF monoclonal antibody bevacizumab was approved in 2004 as a first-line treatment for Cancermetastatic colorectal cancer ( CRC ) in combination with chemotherapy and provided proof of principle for antiangiogenic therapy .
23579861
RNA isolated from formalin fixed Cancerparaffin embedded tumor specimens of patients treated with bevacizumab was subjected to gene expression analysis with quantitative RT-PCR arrays profiling 84 genes implicated in the angiogenic process .
23579861
Furthermore , Cancerhigh EPHB4 tumor levels were associated with decreased median overall survival ( 16 months vs 48 , Log-rank p = 0.012 ) .
23582881
BACKGROUND : The phosphatase and tensin homolog ( PTEN ) tumor suppressor gene is deregulated in Cancermany advanced prostate cancers , leading to activation of the phosphatidylinositol 3-kinase ( PI3K )-Akt-mammalian target of rapamycin ( mTOR ) pathway and thus increased cell survival .
23582881
OBJECTIVE : To evaluate everolimus , an inhibitor of mTOR , in patients with Cancermetastatic castration resistant prostate cancer ( mCRPC ) , and to explore potentially predictive serum biomarkers by proteomics , the significance of PTEN status in tumor tissue , and the impact of everolimus on immune cell subpopulations and function .
23582881
OBJECTIVE : To evaluate everolimus , an inhibitor of mTOR , in patients with metastatic castration resistant prostate cancer ( mCRPC ) , and to explore potentially predictive serum biomarkers by proteomics , the significance of PTEN status in Cancertumor tissue , and the impact of everolimus on immune cell subpopulations and function .
23582881
DESIGN , SETTING , AND PARTICIPANTS : A total of 37 chemotherapy-naive patients with mCRPC and Diseaseprogressive disease were recruited to this single-arm phase 2 trial ( ClinicalTrials.gov identifier NCT00976755 ) .
23585477
CancerMetastatic melanoma is one of the most aggressive forms of cutaneous cancers .
23585477
Metastatic melanoma is one of the most aggressive forms of Cancercutaneous cancers .
23585477
C-MER proto-oncogene tyrosine kinase ( MERTK ) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in Cancervarious malignancies .
23585477
Using both protein immunohistochemistry and microarray analyses , we demonstrate that MERTK expression correlates with Diseasedisease progression .
23585477
MERTK expression was highest in Cancermetastatic melanomas , followed by primary melanomas , while the lowest expression was observed in nevi .
23585477
MERTK expression was highest in metastatic melanomas , followed by Cancerprimary melanomas , while the lowest expression was observed in nevi .
23585477
Additionally , over half of Cancermelanoma cell lines overexpressed MERTK compared with normal human melanocytes ; however , overexpression did not correlate with mutations in BRAF or RAS .
23585477
Stimulation of Cancermelanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK and ERK , PI3K and AKT , and JAK and STAT .
23585477
MERTK inhibition via shRNA reduced MERTK mediated downstream signaling , reduced colony formation by up to 59 % , and diminished Cancertumor volume by 60 % in a human melanoma murine xenograft model .
23585477
MERTK inhibition via shRNA reduced MERTK mediated downstream signaling , reduced colony formation by up to 59 % , and diminished tumor volume by 60 % in a Cancerhuman melanoma murine xenograft model .
23585477
Treatment of Cancermelanoma cells with UNC1062 , a novel MERTK selective small-molecule tyrosine kinase inhibitor , reduced activation of MERTK mediated downstream signaling , induced apoptosis in culture , reduced colony formation in soft agar , and inhibited invasion of melanoma cells .
23585477
Treatment of melanoma cells with UNC1062 , a novel MERTK selective small-molecule tyrosine kinase inhibitor , reduced activation of MERTK mediated downstream signaling , induced apoptosis in culture , reduced colony formation in soft agar , and inhibited invasion of Cancermelanoma cells .
23585477
This work establishes MERTK as a therapeutic target in Cancermelanoma and provides a rationale for the continued development of MERTK targeted therapies .
23598171
BACKGROUND : CancerVarious human cancers have ALK gene translocations , amplifications , or oncogenic mutations , such as anaplastic large-cell lymphoma , inflammatory myofibroblastic tumours , non-small-cell lung cancer ( NSCLC ) , and neuroblastoma .
23598171
BACKGROUND : Various human cancers have ALK gene translocations , amplifications , or oncogenic mutations , such as Canceranaplastic large-cell lymphoma , inflammatory myofibroblastic tumours , non-small-cell lung cancer ( NSCLC ) , and neuroblastoma .
23598171
BACKGROUND : Various human cancers have ALK gene translocations , amplifications , or oncogenic mutations , such as anaplastic large-cell lymphoma , Cancerinflammatory myofibroblastic tumours , non-small-cell lung cancer ( NSCLC ) , and neuroblastoma .
23598171
BACKGROUND : Various human cancers have ALK gene translocations , amplifications , or oncogenic mutations , such as anaplastic large-cell lymphoma , inflammatory myofibroblastic tumours , Cancernon-small-cell lung cancer ( NSCLC ) , and neuroblastoma .
23598171
BACKGROUND : Various human cancers have ALK gene translocations , amplifications , or oncogenic mutations , such as anaplastic large-cell lymphoma , inflammatory myofibroblastic tumours , non-small-cell lung cancer ( NSCLC ) , and Cancerneuroblastoma .
23598171
We aimed to determine the safety , recommended phase 2 dose , and antitumour activity of crizotinib in children with Cancerrefractory solid tumours and anaplastic large-cell lymphoma .
23598171
We aimed to determine the safety , recommended phase 2 dose , and antitumour activity of crizotinib in children with refractory solid tumours and Canceranaplastic large-cell lymphoma .
23598171
METHODS : In this open-label , phase 1 dose escalation trial , patients older than 12 months and younger than 22 years with measurable or evaluable solid or CancerCNS tumours , or anaplastic large-cell lymphoma , refractory to therapy and for whom there was no known curative treatment were eligible .
23598171
METHODS : In this open-label , phase 1 dose escalation trial , patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours , or Canceranaplastic large-cell lymphoma , refractory to therapy and for whom there was no known curative treatment were eligible .
23598171
The primary endpoint was to estimate the maximum tolerated dose , to define the toxic effects of crizotinib , and to characterise the pharmacokinetics of crizotinib in children with Cancerrefractory cancer .
23598171
Additionally , patients with confirmed ALK translocations , mutations , or amplification ( part A2 of the study ) or Cancerneuroblastoma ( part A3 ) could enrol at one dose level lower than was currently given in part A1 .
23598171
We assessed ALK genomic status in Cancertumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma .
23598171
We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with Canceranaplastic large-cell lymphoma .
23598171
All patients who received at least one dose of crizotinib were evaluable for response ; patients completing at least one cycle of therapy or experiencing dose limiting Diseasetoxicity before that were considered fully evaluable for toxicity .
23598171
All patients who received at least one dose of crizotinib were evaluable for response ; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for Diseasetoxicity .
23598171
Grade 4 adverse events in cycle 1 were Diseaseneutropenia ( two ) and liver enzyme elevation ( one ) .
23598171
Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia ( two ) , and Diseaseneutropenia ( eight ) .
23598171
CancerObjective tumour responses were documented in 14 of 79 patients ( nine complete responses , five partial responses ) ; and the anti-tumour activity was enriched in patients with known activating ALK aberrations ( eight of nine with anaplastic large-cell lymphoma , one of 11 with neuroblastoma , three of seven with inflammatory myofibroblastic tumour , and one of two with NSCLC ) .
23598171
Objective tumour responses were documented in 14 of 79 patients ( nine complete responses , five partial responses ) ; and the anti-tumour activity was enriched in patients with known activating ALK aberrations ( eight of nine with Canceranaplastic large-cell lymphoma , one of 11 with neuroblastoma , three of seven with inflammatory myofibroblastic tumour , and one of two with NSCLC ) .
23598171
Objective tumour responses were documented in 14 of 79 patients ( nine complete responses , five partial responses ) ; and the anti-tumour activity was enriched in patients with known activating ALK aberrations ( eight of nine with anaplastic large-cell lymphoma , one of 11 with Cancerneuroblastoma , three of seven with inflammatory myofibroblastic tumour , and one of two with NSCLC ) .
23598171
Objective tumour responses were documented in 14 of 79 patients ( nine complete responses , five partial responses ) ; and the anti-tumour activity was enriched in patients with known activating ALK aberrations ( eight of nine with anaplastic large-cell lymphoma , one of 11 with neuroblastoma , three of seven with Cancerinflammatory myofibroblastic tumour , and one of two with NSCLC ) .
23598171
INTERPRETATION : The findings suggest that a targeted inhibitor of ALK has antitumour activity in Cancerchildhood malignancies harbouring ALK translocations , particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours , and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted .
23598171
INTERPRETATION : The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations , particularly Canceranaplastic large-cell lymphoma and inflammatory myofibroblastic tumours , and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted .
23598171
INTERPRETATION : The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations , particularly anaplastic large-cell lymphoma and Cancerinflammatory myofibroblastic tumours , and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted .
23598171
INTERPRETATION : The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations , particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours , and that further investigation in the subset of Cancerneuroblastoma harbouring known ALK oncogenic mutations is warranted .
23612012
In Cancermultiple myeloma , there has been little progress in the specific therapeutic targeting of oncogenic mutations .
23612012
To uncover the clinical relevance of this mutation in Cancermultiple myeloma , we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome .
23612012
To uncover the clinical relevance of this mutation in multiple myeloma , we correlated the mutation status in Cancerprimary tumor samples from 379 patients with myeloma with disease outcome .
23612012
To uncover the clinical relevance of this mutation in multiple myeloma , we correlated the mutation status in primary tumor samples from 379 patients with Cancermyeloma with disease outcome .
23612012
To uncover the clinical relevance of this mutation in multiple myeloma , we correlated the mutation status in primary tumor samples from 379 patients with myeloma with Diseasedisease outcome .
23612012
We found a significantly higher incidence of Diseaseextramedullary disease and a shorter overall survival in mutation carriers when compared with controls .
23612012
Most importantly , we report on a patient with confirmed BRAF V600E mutation and relapsed Cancermyeloma with extensive extramedullary disease , refractory to all approved therapeutic options , who has rapidly and durably responded to low doses of the mutation specific BRAF inhibitor vermurafenib .
23612012
Most importantly , we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with Diseaseextensive extramedullary disease , refractory to all approved therapeutic options , who has rapidly and durably responded to low doses of the mutation specific BRAF inhibitor vermurafenib .
23619167
Genomic findings underscore the heterogeneity of head and Cancerneck squamous cell carcinoma ( HNSCC ) .
23619167
Analysis of whole-exome sequencing data from 151 Cancertumors revealed the phosphoinositide 3-kinase ( PI3K ) pathway to be the most frequently mutated oncogenic pathway ( 30.5 % ) .
23619167
PI3K pathway mutated CancerHNSCC tumors harbored a significantly higher rate of mutations in known cancer genes .
23619167
PI3K pathway mutated HNSCC tumors harbored a significantly higher rate of mutations in Cancerknown cancer genes .
23619167
In a subset of Cancerhuman papillomavirus positive tumors , PIK3CA or PIK3R1 was the only mutated cancer gene .
23619167
In a subset of human papillomavirus positive tumors , PIK3CA or PIK3R1 was the only mutated Cancercancer gene .
23619167
Strikingly , all Cancertumors with concurrent mutation of multiple PI3K pathway genes were advanced ( stage IV ) , implicating concerted PI3K pathway aberrations in HNSCC progression .
23619944
BACKGROUND : The insulin like growth factor-1 receptor ( IGF-1R ) pathway is known to play a role in the acquisition of resistance to epidermal growth factor receptor ( EGFR )-specific tyrosine kinase inhibitors ( TKIs ) in Cancernon small cell lung cancer ( NSCLC ) .
23619944
In primary NSCLC tissues , IGF-1R expression was found to be significantly higher in patients with Diseaseprogressive disease , i.e. , showing gefitinib resistance , as compared to those with a complete or partial response .
23620406
PURPOSE : To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1 , SETD2 , and BAP1 on Cancercancer specific survival ( CSS ) of 609 patients with clear cell renal cell carcinoma ( ccRCC ) from 2 distinct cohorts .
23620406
PURPOSE : To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1 , SETD2 , and BAP1 on cancer specific survival ( CSS ) of 609 patients with Cancerclear cell renal cell carcinoma ( ccRCC ) from 2 distinct cohorts .
23620406
These findings were compared with analyses of the genomic and clinical dataset from our nonoverlapping The CancerCancer Genome Atlas ( TCGA ) cohort of 421 patients with primary ccRCC .
23620406
BAP1 and SETD2 mutations ( 6 %-12% ) are associated with worse CSS , suggesting their roles in Diseasedisease progression .
23620406
PBRM1 mutations ( 30 %-34% ) do not impact CSS , implicating its principal role in the Cancertumor initiation .
23620515
Inactivation of the switch and sucrose nonfermentable complex component SMARCB1 is extremely prevalent in Cancerpediatric malignant rhabdoid tumors ( MRTs ) or atypical teratoid rhabdoid tumors .
23620515
Inactivation of the switch and sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors ( MRTs ) or Canceratypical teratoid rhabdoid tumors .
23620515
This alteration is hypothesized to confer oncogenic dependency on EZH2 in these Cancercancers .
23620515
Treatment of xenograft bearing mice with ( N-( ( 4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl ) methyl )-5-( ethyl ( tetrahydro-2H-py ran-4-yl ) amino )-4-methyl-4 '-( morpholinomethyl )-[ 1,1 '-biphenyl ]-3-carboxamide ) leads to dose dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3 , and prevention of Cancertumor regrowth after dosing cessation .
23620515
These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2 targeted drugs for the treatment of these genetically defined Cancercancers .
23632886
In this study , we evaluated the frequency and prognostic impact of DNMT3A mutations ( DNMT3A ( mut ) ) in 1770 younger adult patients with Canceracute myeloid leukemia ( AML ) in the context of other genetic alterations and the European LeukemiaNet ( ELN ) classification .
23635773
High-risk types of Cancerhuman papilloma virus ( HPV ) are increasingly associated with oropharyngeal squamous cell carcinoma ( OPSCC ) .
23635773
High-risk types of human papilloma virus ( HPV ) are increasingly associated with Canceroropharyngeal squamous cell carcinoma ( OPSCC ) .
23639470
BACKGROUND : Currently , crizotinib is the only drug that has been approved for treatment of ALK rearranged Cancernon-small-cell lung cancer ( NSCLC ) .
23639470
The primary endpoints of the phase 1 were dose limiting Diseasetoxicity ( DLT ) , maximum tolerated dose ( MTD ) , and pharmacokinetic parameters .
23639470
Treatment was continued in 21-day cycles until Diseasedisease progression , intolerable adverse events , or withdrawal of consent .
23645741
BACKGROUND : Pemetrexed is a key drug for therapy of Cancernon small cell lung cancer ( NSCLC ) .
23645741
RESULTS : TYMS copy numbers in Cancerlung adenocarcinoma cell lines were significantly lower than in squamous cell carcinoma ( p = 0.0105 ) , and a significant correlation was found between the TYMS copy number and the 50 % inhibitory concentration value for pemetrexed in all 17 lung cancer cell lines tested ( r = 0.6814 , p = 0.0026 ) .
23645741
RESULTS : TYMS copy numbers in lung adenocarcinoma cell lines were significantly lower than in Cancersquamous cell carcinoma ( p = 0.0105 ) , and a significant correlation was found between the TYMS copy number and the 50 % inhibitory concentration value for pemetrexed in all 17 lung cancer cell lines tested ( r = 0.6814 , p = 0.0026 ) .
23645741
RESULTS : TYMS copy numbers in lung adenocarcinoma cell lines were significantly lower than in squamous cell carcinoma ( p = 0.0105 ) , and a significant correlation was found between the TYMS copy number and the 50 % inhibitory concentration value for pemetrexed in all 17 Cancerlung cancer cell lines tested ( r = 0.6814 , p = 0.0026 ) .
23645741
CONCLUSION : To our knowledge , this is the first report of a significant association between TYMS copy number and response to pemetrexed treatment in Cancertumor biopsy specimens .
23652803
The pharmacogenetics of methotrexate ( MTX ) was investigated in a large cohort of pediatric patients with Canceracute lymphoblastic leukemia ( ALL ) .
23652803
Patients ' MTX pharmacokinetics , DiseaseMTX toxicities , and outcomes were correlated with the genotypes .
23652803
MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses ( R ( 2 ) = 0.043 ; P < .001 ) , whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of Diseasestomatitis ( R ( 2 ) = 0.018 ; P = .009 ) , a frequent side effect of high-dose MTX .
23652803
Multiple Cox regression analyses revealed an association of Diseaseminimal residual disease ( hazard ratio 7.3 ; P < .001 ) and methylenetetrahydrofolate reductase rs1801131 ( hazard ratio 3.1 ; P = .015 ) with event-free survival in the ALL-BFM 2000 study population .
23656643
BACKGROUND : The molecular causes of Cancermany hematologic cancers remain unclear .
23656643
Among these Cancercancers are chronic neutrophilic leukemia ( CNL ) and atypical ( BCR-ABL1-negative ) chronic myeloid leukemia ( CML ) , both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms .
23656643
Among these cancers are Cancerchronic neutrophilic leukemia ( CNL ) and atypical ( BCR-ABL1-negative ) chronic myeloid leukemia ( CML ) , both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms .
23656643
Among these cancers are chronic neutrophilic leukemia ( CNL ) and atypical ( BCR-ABL1-negative ) Cancerchronic myeloid leukemia ( CML ) , both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms .
23656643
METHODS : To identify potential genetic drivers in these Diseasedisorders , we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase specific small interfering RNAs or small-molecule kinase inhibitors .
23656643
METHODS : To identify potential genetic drivers in these disorders , we used an integrated approach of deep sequencing coupled with the screening of Cancerprimary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase specific small interfering RNAs or small-molecule kinase inhibitors .
23656643
( Funded by the CancerLeukemia and Lymphoma Society and others . )
23656643
( Funded by the Leukemia and CancerLymphoma Society and others . )
23658459
PURPOSE : Fibroblast growth factor receptor 1 ( FGFR1 ) and FGFR2 amplifications are observed in approximately 10 % of Cancerbreast cancers and are related to poor outcomes .
23658459
PURPOSE : Fibroblast growth factor receptor 1 ( FGFR1 ) and FGFR2 amplifications are observed in approximately 10 % of breast cancers and are related to AdverseOutcomepoor outcomes .
23658459
We evaluated whether dovitinib ( TKI258 ) , an inhibitor of FGFR1 , FGFR2 , and FGFR3 , presented antitumor activity in FGFR amplified Cancerbreast cancers .
23658459
EXPERIMENTAL DESIGN : Preclinical activity of dovitinib was evaluated in both Cancerbreast cancer cell lines and an FGFR1 amplified xenograft model ( HBCx2 ) .
23658459
Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2 Cancernegative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor ( HR ) status .
23658459
RESULTS : Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2 amplified , but not FGFR-normal , Cancerbreast cancer cell lines .
23658459
Dovitinib also inhibits Cancertumor growth in FGFR1 amplified breast cancer xenografts .
23658459
Dovitinib also inhibits tumor growth in FGFR1 amplified Cancerbreast cancer xenografts .
23658459
Unconfirmed response or Diseasestable disease for more than 6 months was observed in 5 ( 25 % ) and 1 ( 3 % ) patient ( s ) with FGFR1-amplified and HR-positive and FGFR1-nonamplified and HR-positive breast cancer .
23658459
Unconfirmed response or stable disease for more than 6 months was observed in 5 ( 25 % ) and 1 ( 3 % ) patient ( s ) with FGFR1-amplified and HR-positive and FGFR1-nonamplified and CancerHR-positive breast cancer .
23658459
When qPCR identified amplifications in FGFR1 , FGFR2 , or FGF3 were grouped to define an FGF pathway amplified Cancerbreast cancer in HR positive patients , the mean reduction in target lesions was 21.1 % compared with a 12.0 % increase in patients who did not present with FGF pathway amplified breast cancer .
23658459
When qPCR identified amplifications in FGFR1 , FGFR2 , or FGF3 were grouped to define an FGF pathway amplified breast cancer in HR positive patients , the mean reduction in target lesions was 21.1 % compared with a 12.0 % increase in patients who did not present with FGF pathway amplified Cancerbreast cancer .
23658459
CONCLUSION : Dovitinib showed antitumor activity in FGFR amplified Cancerbreast cancer cell lines and may have activity in breast cancers with FGF pathway amplification .
23658459
CONCLUSION : Dovitinib showed antitumor activity in FGFR amplified breast cancer cell lines and may have activity in Cancerbreast cancers with FGF pathway amplification .
23670176
Since the introduction of all-trans retinoic acid ( ATRA ) and arsenic trioxide ( As2O3 ) for the treatment of Canceracute promyelocytic leukemia ( APL ) , the overall survival rate has improved dramatically .
23674493
PURPOSE : CancerEndometrioid endometrial cancers ( EEC ) frequently harbor coexisting mutations in phosphoinositide 3-kinase ( PI3K ) pathway genes , including PTEN , PIK3CA , PIK3R1 , and KRAS .
23674493
CONCLUSIONS : Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and CancerPTEN-mutant tumors , respectively , even in a subset of EECs concurrently harboring KRAS mutations .
23706910
CancerEwing sarcoma ( ES ) is an aggressive malignant small round cell tumor that arises in bone or soft tissue of adolescents and young adults .
23706910
Ewing sarcoma ( ES ) is an Canceraggressive malignant small round cell tumor that arises in bone or soft tissue of adolescents and young adults .
23724867
BACKGROUND : In patients with Cancermelanoma , ipilimumab ( an antibody against cytotoxic T-lymphocyte-associated antigen 4 [ CTLA-4 ] ) prolongs overall survival , and nivolumab ( an antibody against the programmed death 1 [ PD-1 ] receptor ) produced durable tumor regression in a phase 1 trial .
23724867
BACKGROUND : In patients with melanoma , ipilimumab ( an antibody against cytotoxic T-lymphocyte-associated antigen 4 [ CTLA-4 ] ) prolongs overall survival , and nivolumab ( an antibody against the programmed death 1 [ PD-1 ] receptor ) produced Cancerdurable tumor regression in a phase 1 trial .
23724867
On the basis of their distinct immunologic mechanisms of action and supportive preclinical data , we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with Canceradvanced melanoma .
23724867
Evidence of clinical activity ( conventional , unconfirmed , or immune related response or Diseasestable disease for > = 24 weeks ) was observed in 65 % of patients .
23724867
At the maximum doses that were associated with an acceptable level of adverse events ( nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram ) , 53 % of patients had an objective response , all with Cancertumor reduction of 80 % or more .
23724867
CONCLUSIONS : Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy , with rapid and Cancerdeep tumor regression in a substantial proportion of patients .
23724913
BACKGROUND : In single-group studies , chromosomal rearrangements of the Canceranaplastic lymphoma kinase gene ( ALK ) have been associated with marked clinical responses to crizotinib , an oral tyrosine kinase inhibitor targeting ALK .
23724913
METHODS : We conducted a phase 3 , open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or Cancermetastatic ALK positive lung cancer who had received one prior platinum based regimen .
23724913
Patients in the chemotherapy group who had Diseasedisease progression were permitted to cross over to crizotinib as part of a separate study .
23724913
Common adverse events associated with crizotinib were Diseasevisual disorder , gastrointestinal side effects , and elevated liver aminotransferase levels , whereas common adverse events with chemotherapy were fatigue , alopecia , and dyspnea .
23724913
Patients reported greater reductions in symptoms of Cancerlung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy .
23724913
CONCLUSIONS : Crizotinib is superior to standard chemotherapy in patients with previously treated , advanced Cancernon-small-cell lung cancer with ALK rearrangement .
23724914
Crizotinib , an inhibitor of Canceranaplastic lymphoma kinase ( ALK ) , has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations .
23724914
Crizotinib , an inhibitor of anaplastic lymphoma kinase ( ALK ) , has also recently shown efficacy in the treatment of Cancerlung cancers with ROS1 translocations .
23724914
Resistance to crizotinib developed in a patient with Cancermetastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment .
23724914
We performed a biopsy of a Cancerresistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain .
23729478
EGF receptor ( EGFR )-targeted monoclonal antibodies are effective in a subset of Cancermetastatic colorectal cancers .
23729478
We show that amplification of the MET proto-oncogene is associated with acquired resistance in Cancertumors that do not develop KRAS mutations during anti-EGFR therapy .
23729478
Amplification of the MET locus was present in circulating Cancertumor DNA before relapse was clinically evident .
23729478
Notably , in patient derived Cancercolorectal cancer xenografts , MET amplification correlated with resistance to EGFR blockade , which could be overcome by MET kinase inhibitors .
23729478
These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in Cancercolorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification .
23746666
BACKGROUND : Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or Cancermetastatic squamous-cell carcinoma of the head and neck ( SCCHN ) .
23746666
Eligible patients were aged at least 18 years ; had histologically or cytologically confirmed SCCHN ; had distant metastatic or locoregionally Diseaserecurrent disease , or both , that was deemed to be incurable by surgery or radiotherapy ; had an Eastern Cooperative Oncology Group performance status of 1 or less ; and had adequate haematological , renal , hepatic , and cardiac function .
23746666
Patients were randomly assigned according to a computer generated randomisation sequence ( 1:1 ; stratified by previous treatment , Cancerprimary tumour site , and performance status ) to one of two groups .
23746666
In a prospectively defined retrospective analysis , we assessed Cancertumour human papillomavirus ( HPV ) status as a potential predictive biomarker of outcomes with a validated p16-INK4A ( henceforth , p16 ) immunohistochemical assay .
23746666
Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group : skin or Diseaseeye toxicity ( 62 [ 19 % ] of 325 included in safety analyses vs six [ 2 % ] of 325 ) , diarrhoea ( 15 [ 5 % ] vs four [ 1 % ] ) , hypomagnesaemia ( 40 [ 12 % ] vs 12 [ 4 % ] ) , hypokalaemia ( 33 [ 10 % ] vs 23 [ 7 % ] ) , and dehydration ( 16 [ 5 % ] vs seven [ 2 % ] ) .
23746666
Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group : skin or eye toxicity ( 62 [ 19 % ] of 325 included in safety analyses vs six [ 2 % ] of 325 ) , diarrhoea ( 15 [ 5 % ] vs four [ 1 % ] ) , Diseasehypomagnesaemia ( 40 [ 12 % ] vs 12 [ 4 % ] ) , hypokalaemia ( 33 [ 10 % ] vs 23 [ 7 % ] ) , and dehydration ( 16 [ 5 % ] vs seven [ 2 % ] ) .
23746666
Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group : skin or eye toxicity ( 62 [ 19 % ] of 325 included in safety analyses vs six [ 2 % ] of 325 ) , diarrhoea ( 15 [ 5 % ] vs four [ 1 % ] ) , hypomagnesaemia ( 40 [ 12 % ] vs 12 [ 4 % ] ) , Diseasehypokalaemia ( 33 [ 10 % ] vs 23 [ 7 % ] ) , and dehydration ( 16 [ 5 % ] vs seven [ 2 % ] ) .
23746666
Median overall survival in patients with Cancerp16 negative tumours was longer in the panitumumab group than in the control group ( 11.7 months [ 95 % CI 9.7-13 .7 ] vs 8.6 months [ 6.9-11 .1 ] ; HR 0.73 [ 95 % CI 0.58-0 .93 ] ; p = 0.0115 ) , but this difference was not shown for p16 positive patients ( 11.0 months [ 7.3-12 .9 ] vs 12.6 months [ 7.7-17 .4 ] ; 1.00 [ 0.62-1 .61 ] ; p = 0.998 ) .
23746666
INTERPRETATION : Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN , it improved progression-free survival and had an Diseaseacceptable toxicity profile .
23761041
Disabling mutations in the gene encoding ATM occur frequently in Cancervarious human tumors , including lung cancer and hematological malignancies .
23761041
Disabling mutations in the gene encoding ATM occur frequently in various human tumors , including Cancerlung cancer and hematological malignancies .
23761041
Disabling mutations in the gene encoding ATM occur frequently in various human tumors , including lung cancer and Cancerhematological malignancies .
23761041
We report that ATM deficiency prevents apoptosis in human and Cancermurine cancer cells exposed to genotoxic chemotherapy .
23761041
Finally , we demonstrate that DNA-PKcs inhibitors are effective as single agents against CancerATM defective lymphomas in vivo .
23761041
Together , our data implicate DNA-PKcs as a drug target for the treatment of CancerATM defective malignancies .
23764753
Recently , de4 EGFR , a variant of epidermal growth factor receptor ( EGFR ) with exon 4 deletion , was identified in Cancerglioblastoma and ovarian cancer .
23764753
Recently , de4 EGFR , a variant of epidermal growth factor receptor ( EGFR ) with exon 4 deletion , was identified in glioblastoma and Cancerovarian cancer .
23764753
However , its biological function on Cancerovarian cancer is still not clear .
23764753
In this study , the expression profile of de4 EGFR and its contribution to Cancerepithelial ovarian cancer cells proliferation , invasiveness and drug resistance were studied .
23764753
Our results showed that 48.6 % ( 35/72 ) of Cancerepithelial ovarian cancer tissues had de4 EGFR expression and the expression ratio positively correlated with clinical stages .
23764753
Collectively , these results demonstrate that de4 EGFR plays an important role in the invasiveness and cisplatin resistance in Cancerepithelial ovarian cancer cells and may provide a new potential therapeutic target for epithelial ovarian cancer .
23764753
Collectively , these results demonstrate that de4 EGFR plays an important role in the invasiveness and cisplatin resistance in epithelial ovarian cancer cells and may provide a new potential therapeutic target for Cancerepithelial ovarian cancer .
23766237
Mutations 1 295 228 C > T and 1 295 250 C > T ( termed C228T and C250T respectively ) , corresponding to -124 C > T and -146 C > T from the translation start site in the promoter of the telomerase reverse transcriptase ( TERT ) gene , have recently been reported in Cancerhuman cancers , but not in thyroid cancers yet .
23766237
Mutations 1 295 228 C > T and 1 295 250 C > T ( termed C228T and C250T respectively ) , corresponding to -124 C > T and -146 C > T from the translation start site in the promoter of the telomerase reverse transcriptase ( TERT ) gene , have recently been reported in human cancers , but not in Cancerthyroid cancers yet .
23766237
We explored these mutations in Cancerthyroid cancers by genomic sequencing of a large number of primary tumor samples .
23766237
We explored these mutations in thyroid cancers by genomic sequencing of a large number of Cancerprimary tumor samples .
23766237
We found the C228T mutation in 0 of 85 ( 0.0 % ) Cancerbenign thyroid tumors , 30 of 257 ( 11.7 % ) papillary thyroid cancers ( PTC ) , 9 of 79 ( 11.4 % ) follicular thyroid cancers ( FTC ) , 3 of 8 ( 37.5 % ) poorly differentiated thyroid cancers ( PDTC ) , 23 of 54 ( 42.6 % ) anaplastic thyroid cancers ( ATC ) , and 8 of 12 ( 66.7 % ) thyroid cancer cell lines .
23766237
We found the C228T mutation in 0 of 85 ( 0.0 % ) benign thyroid tumors , 30 of 257 ( 11.7 % ) Cancerpapillary thyroid cancers ( PTC ) , 9 of 79 ( 11.4 % ) follicular thyroid cancers ( FTC ) , 3 of 8 ( 37.5 % ) poorly differentiated thyroid cancers ( PDTC ) , 23 of 54 ( 42.6 % ) anaplastic thyroid cancers ( ATC ) , and 8 of 12 ( 66.7 % ) thyroid cancer cell lines .
23766237
We found the C228T mutation in 0 of 85 ( 0.0 % ) benign thyroid tumors , 30 of 257 ( 11.7 % ) papillary thyroid cancers ( PTC ) , 9 of 79 ( 11.4 % ) Cancerfollicular thyroid cancers ( FTC ) , 3 of 8 ( 37.5 % ) poorly differentiated thyroid cancers ( PDTC ) , 23 of 54 ( 42.6 % ) anaplastic thyroid cancers ( ATC ) , and 8 of 12 ( 66.7 % ) thyroid cancer cell lines .
23766237
We found the C228T mutation in 0 of 85 ( 0.0 % ) benign thyroid tumors , 30 of 257 ( 11.7 % ) papillary thyroid cancers ( PTC ) , 9 of 79 ( 11.4 % ) follicular thyroid cancers ( FTC ) , 3 of 8 ( 37.5 % ) poorly differentiated Cancerthyroid cancers ( PDTC ) , 23 of 54 ( 42.6 % ) anaplastic thyroid cancers ( ATC ) , and 8 of 12 ( 66.7 % ) thyroid cancer cell lines .
23766237
We found the C228T mutation in 0 of 85 ( 0.0 % ) benign thyroid tumors , 30 of 257 ( 11.7 % ) papillary thyroid cancers ( PTC ) , 9 of 79 ( 11.4 % ) follicular thyroid cancers ( FTC ) , 3 of 8 ( 37.5 % ) poorly differentiated thyroid cancers ( PDTC ) , 23 of 54 ( 42.6 % ) Canceranaplastic thyroid cancers ( ATC ) , and 8 of 12 ( 66.7 % ) thyroid cancer cell lines .
23766237
We found the C228T mutation in 0 of 85 ( 0.0 % ) benign thyroid tumors , 30 of 257 ( 11.7 % ) papillary thyroid cancers ( PTC ) , 9 of 79 ( 11.4 % ) follicular thyroid cancers ( FTC ) , 3 of 8 ( 37.5 % ) poorly differentiated thyroid cancers ( PDTC ) , 23 of 54 ( 42.6 % ) anaplastic thyroid cancers ( ATC ) , and 8 of 12 ( 66.7 % ) Cancerthyroid cancer cell lines .
23766237
The C250T mutation was uncommon , but mutually exclusive with the C228T mutation , and the two mutations were collectively found in 11 of 79 ( 13.9 % ) FTC , 25 of 54 ( 46.3 % ) ATC , and 11 of 12 ( 91.7 % ) Cancerthyroid cancer cell lines .
23766237
No TERT mutation was found in 16 Cancermedullary thyroid cancer samples .
23766237
We thus for the first time , to our knowledge , demonstrate TERT promoter mutations in Cancerthyroid cancers , that are particularly prevalent in the aggressive thyroid cancers TCPTC , PDTC , ATC and BRAF mutation positive PTC , revealing a novel genetic background for thyroid cancers .
23766237
We thus for the first time , to our knowledge , demonstrate TERT promoter mutations in thyroid cancers , that are particularly prevalent in the Canceraggressive thyroid cancers TCPTC , PDTC , ATC and BRAF mutation positive PTC , revealing a novel genetic background for thyroid cancers .
23766237
We thus for the first time , to our knowledge , demonstrate TERT promoter mutations in thyroid cancers , that are particularly prevalent in the aggressive thyroid cancers TCPTC , PDTC , ATC and BRAF mutation positive PTC , revealing a novel genetic background for Cancerthyroid cancers .
23775962
PURPOSE : Amplifications and mutations in the KIT proto-oncogene in subsets of Cancermelanomas provide therapeutic opportunities .
23775962
PATIENTS AND METHODS : We conducted a multicenter phase II trial of imatinib in metastatic mucosal , acral , or chronically sun damaged ( CSD ) Cancermelanoma with KIT amplifications and/or mutations .
23775962
Dose reductions were permitted for Diseasetreatment related toxicities .
23775962
Eight patients ( 33 % ) had Cancertumors with KIT mutations , 11 ( 46 % ) with KIT amplifications , and five ( 21 % ) with both .
23775962
There were no statistical differences in rates of progression or survival by mutation status or by Cancermelanoma site .
23775962
The Diseaseoverall disease control rate was 50 % but varied significantly by KIT mutation status ( 77 % mutated v 18 % amplified ) .
23775962
CONCLUSION : CancerMelanomas that arise on mucosal , acral , or CSD skin should be assessed for KIT mutations .
23775962
Imatinib can be effective when Cancertumors harbor KIT mutations , but not if KIT is amplified only .
23779130
Despite the impressive clinical activity of the second generation antiandrogens enzalutamide and ARN-509 in patients with Cancerprostate cancer , acquired resistance invariably emerges .
23779130
AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of Cancercastration resistant prostate cancer ( CRPC ) .
23779130
Thus , selective outgrowth of AR F876L is a clinically relevant mechanism of second generation antiandrogen resistance that can potentially be targeted with next generation antiandrogens.SIGNIFICANCE : A missense mutation in the ligand binding domain of the androgen receptor F876L confers resistance to the second generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and Cancerprostate cancer and is detected in plasma DNA from ARN-509-treated patients with progressive disease .
23779130
Thus , selective outgrowth of AR F876L is a clinically relevant mechanism of second generation antiandrogen resistance that can potentially be targeted with next generation antiandrogens.SIGNIFICANCE : A missense mutation in the ligand binding domain of the androgen receptor F876L confers resistance to the second generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARN-509-treated patients with Diseaseprogressive disease .
23792563
Genetic changes underlying Cancerclear cell renal cell carcinoma ( ccRCC ) include alterations in genes controlling cellular oxygen sensing ( for example , VHL ) and the maintenance of chromatin states ( for example , PBRM1 ) .
23792563
We surveyed more than 400 Cancertumours using different genomic platforms and identified 19 significantly mutated genes .
23792563
CancerAggressive cancers demonstrated evidence of a metabolic shift , involving downregulation of genes involved in the TCA cycle , decreased AMPK and PTEN protein levels , upregulation of the pentose phosphate pathway and the glutamine transporter genes , increased acetyl-CoA carboxylase protein , and altered promoter methylation of miR-21 ( also known as MIR21 ) and GRB10 .
23792563
Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with Cancertumour stage and severity and offers new views on the opportunities for disease treatment .
23792563
Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for Diseasedisease treatment .
23793026
Gene expression profiles and chromosome 3 Cancercopy number divide uveal melanomas into two distinct classes correlating with prognosis .
23793026
Using exome sequencing , we identified recurrent somatic mutations in EIF1AX and SF3B1 , specifically occurring in Canceruveal melanomas with disomy 3 , which rarely metastasize .
23793026
Targeted resequencing showed that 24 of 31 Cancertumors with disomy 3 ( 77 % ) had mutations in either EIF1AX ( 15 ; 48 % ) or SF3B1 ( 9 ; 29 % ) .
23793026
Mutations were infrequent ( 2/35 ; 5.7 % ) in Canceruveal melanomas with monosomy 3 , which are associated with poor prognosis .
23793026
Mutations were infrequent ( 2/35 ; 5.7 % ) in uveal melanomas with monosomy 3 , which are associated with AdverseOutcomepoor prognosis .
23793026
Resequencing of 13 Canceruveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 ( 7 ; 54 % ) or EIF1AX ( 1 ; 8 % ) .
23793026
Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 Cancertumors with a mutation in either SF3B1 ( 7 ; 54 % ) or EIF1AX ( 1 ; 8 % ) .
23793026
Resequencing of ten Canceruveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors , none of which targeted Arg625 .
23793026
Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three Cancertumors , none of which targeted Arg625 .
23797736
CancerClear-cell renal cell carcinoma ( ccRCC ) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood .
23797736
Clear-cell renal cell carcinoma ( ccRCC ) is the most Cancerprevalent kidney cancer and its molecular pathogenesis is incompletely understood .
23797736
We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on Cancertumor behavior .
23797736
This integrated molecular analysis unmasked new correlations between DNA methylation , gene mutation and/or gene expression and copy number profiles , enabling the stratification of AdverseOutcomeclinical risks for patients with ccRCC .
23800680
CancerEwing sarcoma occurs in children , adolescents and young adults .
23800680
High STAT3 levels have been reported in approximately 50 % of patients with CancerEwing sarcoma , and may be important in tumorigenesis .
23800680
To date , while somatic mutations in PTPRD have been reported in Cancerdiverse tumors , germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers .
23800680
To date , while somatic mutations in PTPRD have been reported in diverse tumors , germline mutations of PTPRD have not been investigated in CancerEwing sarcoma or other cancers .
23800680
To date , while somatic mutations in PTPRD have been reported in diverse tumors , germline mutations of PTPRD have not been investigated in Ewing sarcoma or Cancerother cancers .
23800680
We identified a novel germline mutation in the PTPRD gene in three of eight patients ( 37.5 % ) with Cancermetastatic Ewing sarcoma .
23800680
Our pilot data suggest that PTPRD germline mutations may play a role in the development of CancerEwing sarcoma , a disease of young people , and their presence may have implications for therapy .
23800680
Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma , a Diseasedisease of young people , and their presence may have implications for therapy .
23802768
AIMS : Preclinical data suggest that signalling through the HGF-MET pathway may confer resistance to BRAF inhibition in BRAF ( V600E/K ) Cancermelanoma .
23802768
Therefore , blockade of HGF-MET signalling might be a valid therapeutic strategy , in combination with BRAF inhibition , in BRAF ( V600E/K ) Cancermelanoma .
23802768
The aim of this study was to investigate the clinical relevance of these observations by evaluating the survival impact of MET expression in patients with BRAF ( V600E/K ) advanced Cancermelanoma treated with vemurafenib .
23802768
METHODS AND RESULTS : Formalin fixed tissue blocks were obtained of Cancertumours from patients enrolled in the BRIM2 ( n = 59 ) and BRIM3 ( n = 150 ) trials of vemurafenib in advanced BRAF ( V600E/K ) melanoma .
23802768
METHODS AND RESULTS : Formalin fixed tissue blocks were obtained of tumours from patients enrolled in the BRIM2 ( n = 59 ) and BRIM3 ( n = 150 ) trials of vemurafenib in advanced BRAF ( V600E/K ) Cancermelanoma .
23802768
CONCLUSIONS : MET is expressed in a proportion of BRAF ( V600E/K ) advanced Cancermelanomas .
23802768
Further analyses on appropriately powered subsets are needed to determine the prognostic and predictive significance of MET in vemurafenib treated Cancermelanoma .
23806793
We aimed to investigate the prevalence and prognostic significance of alterations in FGFR1 copy number in Cancernon small cell lung cancer ( NSCLC ) .
23806793
High FGFR1 gene copy number ( amplification or high-level polysomy ) was significantly more frequent in Cancersquamous cell carcinomas ( SCC ) ( 24.8 % ) and large cell carcinomas ( LCC ) ( 25 % ) compared to adenocarcinomas ( 11.3 % ) ( p = 0.01 and p = 0.03 respectively ) .
23806793
High FGFR1 gene copy number ( amplification or high-level polysomy ) was significantly more frequent in squamous cell carcinomas ( SCC ) ( 24.8 % ) and Cancerlarge cell carcinomas ( LCC ) ( 25 % ) compared to adenocarcinomas ( 11.3 % ) ( p = 0.01 and p = 0.03 respectively ) .
23806793
High FGFR1 gene copy number ( amplification or high-level polysomy ) was significantly more frequent in squamous cell carcinomas ( SCC ) ( 24.8 % ) and large cell carcinomas ( LCC ) ( 25 % ) compared to Canceradenocarcinomas ( 11.3 % ) ( p = 0.01 and p = 0.03 respectively ) .
23806793
Among NSCLC there was no significant correlation between FGFR1 positive status and other clinicopathological features including age , gender , smoking history , Cancertumour size , lymph node status , stage , grade , vascular , lymphatic or perineural invasion .
23806793
Multivariate survival analysis using Cox regression model confirmed FGFR1 positive patients had a significant reduction in the AdverseOutcomerisk of death compared to FGFR1 negative patients ( HR 0.6 ; p = 0.02 ) .
23812671
PURPOSE : For patients with Canceradvanced melanoma , primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges .
23812671
One rationale argues that novel biologically informed strategies are needed to maximally cripple Cancermelanoma cells up front before compensatory mechanisms emerge .
23812671
As p53 is uncommonly mutated in Cancermelanoma , restoration of its function represents an attractive adjunct to selective BRAF inhibition .
23812671
EXPERIMENTAL DESIGN : Thirty-seven BRAF ( CancerV600E )-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 ( Nt-3 ) .
23812671
RESULTS : Dual targeting of BRAF ( V600E ) and Hdm2 with vemurafenib and Nt-3 , respectively , synergistically induced apoptosis and suppressed Cancermelanoma viability in vitro and tumor growth in vivo .
23812671
RESULTS : Dual targeting of BRAF ( V600E ) and Hdm2 with vemurafenib and Nt-3 , respectively , synergistically induced apoptosis and suppressed melanoma viability in vitro and Cancertumor growth in vivo .
23812671
Suppression of p53 in Cancermelanoma cells abrogated Nt-3 's effects fully and vemurafenib 's effects partially .
23816960
A phase II study of afatinib in CancerEGFR mutation positive lung adenocarcinoma demonstrated high response rates and progression-free survival ( PFS ) .
23816960
PATIENTS AND METHODS : In this phase III study , eligible patients with Cancerstage IIIB/IV lung adenocarcinoma were screened for EGFR mutations .
23816960
Secondary end points included Cancertumor response , overall survival , adverse events , and patient reported outcomes ( PROs ) .
23816960
The most common treatment related adverse events were diarrhea , rash and acne , and Diseasestomatitis for afatinib and nausea , fatigue , and decreased appetite for chemotherapy .
23816960
CONCLUSION : Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with Canceradvanced lung adenocarcinoma and EGFR mutations .
23828442
The significance of KRAS in Canceradvanced colorectal cancer ( CRC ) treated with bevacizumab ( B ) is not well understood .
23845441
We show that BRAF ( V600E ) initiates an alternative pathway to Cancercolorectal cancer ( CRC ) , which progresses through a hyperplasia/adenoma/carcinoma sequence .
23845441
We show that BRAF ( V600E ) initiates an alternative pathway to colorectal cancer ( CRC ) , which progresses through a Cancerhyperplasia/adenoma/carcinoma sequence .
23845441
Genetic and functional analyses in mice revealed a series of stage specific molecular alterations driving different phases of Cancertumor evolution and uncovered mechanisms underlying this stage specificity .
23845441
We further demonstrate dose dependent effects of oncogenic signaling , with physiologic Braf ( V600E ) expression being sufficient for hyperplasia induction , but later stage intensified Mapk signaling driving both Cancertumor progression and activation of intrinsic tumor suppression .
23845441
We further demonstrate dose dependent effects of oncogenic signaling , with physiologic Braf ( V600E ) expression being sufficient for hyperplasia induction , but later stage intensified Mapk signaling driving both tumor progression and activation of Cancerintrinsic tumor suppression .
23845441
Such phenomena explain , for example , the inability of p53 to restrain Cancertumor initiation as well as its importance in invasiveness control , and the late stage specificity of its somatic mutation .
23861105
We aimed to analyze clinical impacts of the U2AF1 mutation on patients with Diseasemyelodysplastic syndrome ( MDS ) and its stability during disease progression .
23861105
We aimed to analyze clinical impacts of the U2AF1 mutation on patients with myelodysplastic syndrome ( MDS ) and its stability during Diseasedisease progression .
23861105
We also sequentially analyzed the U2AF1 mutation in 421 samples from 142 patients to determine its stability during the Diseasedisease courses .
23861105
Sequential analyses showed all original U2AF1 mutations in U2AF1 mutated patients were retained during follow-ups unless complete remission was achieved , whereas none of the U2AF1-wild patients acquired a novel mutation during Diseasedisease evolution .
23861105
The mutation may be used as a biomarker for AdverseOutcomerisk stratification .
23861977
According to the prevailing multistep model of Cancermelanoma development , oncogenic BRAF or NRAS mutations are crucial initial events in melanoma development .
23861977
According to the prevailing multistep model of melanoma development , oncogenic BRAF or NRAS mutations are crucial initial events in Cancermelanoma development .
23861977
It is not known whether melanocytic nevi that are found in association with a Cancermelanoma are more likely to carry BRAF or NRAS mutations than uninvolved nevi .
23861977
By laser microdissection we were able to selectively dissect and genotype cells either from the nevus or from the Cancermelanoma part of 46 melanomas that developed in association with a nevus .
23861977
By laser microdissection we were able to selectively dissect and genotype cells either from the nevus or from the melanoma part of 46 Cancermelanomas that developed in association with a nevus .
23861977
The BRAF ( V600E ) mutation was found in 63.0 % of Cancermelanomas , 65.2 % of associated nevi and 50.0 % of control nevi .
23861977
No significant differences in the distribution of BRAF or NRAS mutations could be found between Cancermelanoma and associated nevi or between melanoma associated nevi and control nevi .
23861977
No significant differences in the distribution of BRAF or NRAS mutations could be found between melanoma and associated nevi or between Cancermelanoma associated nevi and control nevi .
23861977
In concordant cases immunohistochemistry showed a higher expression ( intensity of immunohistochemistry ) of the mutated BRAF ( V600E )-protein in Cancermelanomas compared to their associated nevi .
23861977
In this series the presence of a BRAF- or NRAS mutation in a nevus was not associated with the AdverseOutcomerisk of malignant transformation .
23861977
Our findings do not support the current traditional model of Cancerstepwise tumor progression .
23867504
CancerMetastasis associated phosphatase of regenerating liver-3 ( PRL-3 ) has pleiotropic effects in driving cancer progression , yet the signaling mechanisms of PRL-3 are still not fully understood .
23867504
Metastasis associated phosphatase of regenerating liver-3 ( PRL-3 ) has pleiotropic effects in driving Cancercancer progression , yet the signaling mechanisms of PRL-3 are still not fully understood .
23867504
Here , we provide evidence for PRL-3-induced hyperactivation of EGFR and its downstream signaling cascades in Cancermultiple human cancer cell lines .
23867504
Of clinical significance , we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a Cancerheterogeneous colorectal cancer ( CRC ) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab .
23867504
The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting CancerPRL-3-driven cancer progression .
23867504
We propose that elevated PRL-3 expression is an important clinical predictive biomarker for Cancerfavorable anti-EGFR cancer therapy .
23881388
High levels of Tissue Inhibitor of Metalloproteinases-1 ( TIMP1 ) are associated with AdverseOutcomepoor prognosis , reduced response to chemotherapy , and , potentially , also poor response to endocrine therapy in breast cancer patients .
23881388
High levels of Tissue Inhibitor of Metalloproteinases-1 ( TIMP1 ) are associated with poor prognosis , reduced response to chemotherapy , and , potentially , also poor response to endocrine therapy in Cancerbreast cancer patients .
23881388
Our findings in vitro may have clinical implications as the data suggest that Cancerhigh tumor levels of TIMP1 may be a predictive biomarker for reduced response to fulvestrant .
23881929
PURPOSE : Inactivation of von Hippel-Lindau ( VHL ) gene in Cancerclear-cell renal cell carcinoma ( RCC ) leads to increased levels of hypoxia inducible factors ( HIF ) and overexpression of HIF target genes , such as VEGF and others .
23881929
EXPERIMENTAL DESIGN : We analyzed Cancertumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616 .
23881929
RESULTS : The VEG102616 trial enrolled 225 patients , from whom 78 samples were available for Cancertumor DNA extraction .
23881929
The HIF-1alpha transcriptional signature ( 46 samples ) was enriched in Cancertumors expressing high HIF-1alpha levels .
23888070
PURPOSE : Activating mutations in the phosphoinositide-3-kinase ( PI3K )/AKT/mTOR pathway are present in the majority of Cancerbreast cancers and therefore are a major focus of drug development and clinical trials .
23888070
EXPERIMENTAL DESIGN : We describe the creation of a Cancerphysiologic human luminal breast cancer cell line model to study the phenotype of these mutations using the MCF-7 cell line .
23888070
Knockin of the AKT1 E17K hotspot mutation on this PIK3CA wild-type background restored pathway signaling , proliferation , and Cancertumor growth in vivo .
23888070
CONCLUSIONS : AKT1 E17K is a bona fide oncogene in a Cancerhuman luminal breast cancer context .
23888070
These findings have implications for the use of Cancertumor genome sequencing to assign patients to targeted therapies .
23890088
BRAF is the most prevalent oncogene and an important therapeutic target in Cancermelanoma .
23890088
In some Cancercancers , BRAF is activated by rearrangements that fuse its kinase domain to 5 ' partner genes .
23890088
We examined 848 comparative genomic hybridization profiles of Cancermelanocytic tumors and found copy number transitions within BRAF in 10 tumors , of which six could be further characterized by sequencing .
23890088
We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 Cancertumors , of which six could be further characterized by sequencing .
23890088
No other mutations were identified in Cancermelanoma oncogenes .
23890088
One of the seven Cancermelanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion , which constitutively activated the MAP kinase pathway .
23890088
Sorafenib , but not vemurafenib , could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations , whereas BRAF ( V ) ( 600E ) Cancermutant melanoma cell lines were significantly more sensitive to vemurafenib .
23898052
BACKGROUND : PD-0332991 is an inhibitor of cyclin dependent kinases ( CDK ) 4 and 6 , and was evaluated to determine its anti-proliferative effects in 25 Cancerrenal cell carcinoma ( RCC ) cell lines .
23898052
MATERIALS AND METHODS : Half-maximal inhibitory concentrations ( IC50 ) of PD-0332991 were determined with cell line proliferation assays , as were its effects on the cell cycle , apoptosis , and Cancerretinoblastoma ( RB ) phosphorylation .
23904111
Mutation and loss of Diseasealpha-thalassemia and mental retardation syndrome X linked ( ATRX ) expression has been described in anaplastic gliomas .
23904111
Mutation and loss of alpha-thalassemia and Diseasemental retardation syndrome X linked ( ATRX ) expression has been described in anaplastic gliomas .
23904111
Mutation and loss of alpha-thalassemia and mental retardation syndrome X linked ( ATRX ) expression has been described in Canceranaplastic gliomas .
23904111
The present study explored the role of ATRX status in the molecular classification of Canceranaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial .
23904111
The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the CancerNOA-04 anaplastic glioma trial .
23904111
Loss of ATRX expression was detected in 45 % of Canceranaplastic astrocytomas ( AA ) , 27 % of anaplastic oligoastrocytomas ( AOA ) and 10 % of anaplastic oligodendrogliomas ( AO ) .
23904111
Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas ( AA ) , 27 % of Canceranaplastic oligoastrocytomas ( AOA ) and 10 % of anaplastic oligodendrogliomas ( AO ) .
23904111
Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas ( AA ) , 27 % of anaplastic oligoastrocytomas ( AOA ) and 10 % of Canceranaplastic oligodendrogliomas ( AO ) .
23904111
It was mostly restricted to CancerIDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion .
23904111
Survival analysis showed a marked separation of CancerIDH mutant astrocytic tumors into two groups based on ATRX status : tumors with ATRX loss had a significantly better prognosis ( median time to treatment failure 55.6 vs. 31.8 months , p = 0.0168 , log rank test ) .
23904111
Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status : Cancertumors with ATRX loss had a significantly better prognosis ( median time to treatment failure 55.6 vs. 31.8 months , p = 0.0168 , log rank test ) .
23904111
ATRX status helps better define the clinically and morphologically mixed group of AOA , since ATRX loss is a hallmark of Cancerastrocytic tumors .
23904111
Furthermore , ATRX loss defines a subgroup of Cancerastrocytic tumors with a favorable prognosis .
23934108
As these Cancertumours represent an area of high unmet medical need , multiple allosteric MEK inhibitors , which inhibit MAPK signalling in both genotypes , are being tested in clinical trials .
23934108
Impressive single-agent activity in CancerBRAF-mutant melanoma has been observed ; however , efficacy has been far less robust in KRAS-mutant disease .
23934108
Impressive single-agent activity in BRAF-mutant melanoma has been observed ; however , efficacy has been far less robust in DiseaseKRAS-mutant disease .
23934108
Here we show that , owing to distinct mechanisms regulating MEK activation in KRAS- versus CancerBRAF driven tumours , different mechanisms of inhibition are required for optimal antitumour activity in each genotype .
23934108
Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS driven Cancertumours ( GDC-0623 and G-573 , the former currently in phase I clinical trials ) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF .
23934108
Conversely , potent inhibition of active , phosphorylated MEK is required for strong inhibition of the MAPK pathway in CancerBRAF-mutant tumours , resulting in superior efficacy in this genotype with GDC-0973 ( also known as cobimetinib ) , a MEK inhibitor currently in phase III clinical trials .
23934108
Our study highlights that differences in the activation state of MEK in CancerKRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK .
23934108
Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus CancerBRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK .
23955565
Mutations in the core promoter region of the TERT gene , which increases promoter activity , have been reported in Cancermelanomas and a variety of human neoplasms , including gliomas .
23955565
Mutations in the core promoter region of the TERT gene , which increases promoter activity , have been reported in melanomas and a variety of human neoplasms , including Cancergliomas .
23955565
In the present study , we screened for TERT promoter mutations by direct DNA sequencing in a population based collection of 358 Cancerglioblastomas .
23955565
TERT promoter mutations ( C228T , C250T ) were detected in 55 Cancer% glioblastomas analysed .
23955565
Of these , 73 % had a C228T mutation , and 27 % had a C250T mutation ; only one Cancerglioblastoma had both C228T and C250T mutations .
23955565
TERT promoter mutations were significantly more frequent in primary ( IDH1 wild-type ) Cancerglioblastomas ( 187/322 ; 58 % ) than in secondary ( IDH1 mutated ) glioblastomas ( 10/36 , 28 % ; P = 0.0056 ) .
23955565
TERT promoter mutations were significantly more frequent in primary ( IDH1 wild-type ) glioblastomas ( 187/322 ; 58 % ) than in secondary ( IDH1 mutated ) Cancerglioblastomas ( 10/36 , 28 % ; P = 0.0056 ) .
23955565
CancerGlioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis ( median , 9.3 vs. 10.5 months ; P = 0.015 ) and multivariate analysis after adjusting for age and gender ( HR 1.38 , 95 % CI 1.01-1 .88 , P = 0.041 ) .
23955565
However , TERT mutations had no significant impact on patients ' survival in multivariate analysis after further adjusting for other genetic alterations , or when primary and Cancersecondary glioblastomas were separately analysed .
23955565
These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations , which are a significant prognostic marker of better survival in patients with Cancersecondary glioblastomas .
23960094
The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in Cancermalignant glioma and metastasized melanoma therapy is O ( 6 )-methylguanine ( O ( 6 )-MeG ) .
23960094
The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in malignant glioma and metastasized Cancermelanoma therapy is O ( 6 )-methylguanine ( O ( 6 )-MeG ) .
23960094
We show that ( i ) ATM- and ATR mutated cells are hypersensitive to temozolomide , ( ii ) O ( 6 )-MeG triggers ATM and ATR activation , ( iii ) knockdown of ATM and ATR enhances cell kill in Cancergliobalstoma and malignant melanoma cells with a stronger and significant effect in ATR knockdown cells , ( iv ) ATR , but not ATM , knockdown abolished phosphorylation of H2AX , CHK1 , and CHK2 in glioma cells , and ( v ) temozolomide induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2 .
23960094
We show that ( i ) ATM- and ATR mutated cells are hypersensitive to temozolomide , ( ii ) O ( 6 )-MeG triggers ATM and ATR activation , ( iii ) knockdown of ATM and ATR enhances cell kill in gliobalstoma and Cancermalignant melanoma cells with a stronger and significant effect in ATR knockdown cells , ( iv ) ATR , but not ATM , knockdown abolished phosphorylation of H2AX , CHK1 , and CHK2 in glioma cells , and ( v ) temozolomide induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2 .
23960094
We show that ( i ) ATM- and ATR mutated cells are hypersensitive to temozolomide , ( ii ) O ( 6 )-MeG triggers ATM and ATR activation , ( iii ) knockdown of ATM and ATR enhances cell kill in gliobalstoma and malignant melanoma cells with a stronger and significant effect in ATR knockdown cells , ( iv ) ATR , but not ATM , knockdown abolished phosphorylation of H2AX , CHK1 , and CHK2 in Cancerglioma cells , and ( v ) temozolomide induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2 .
23960094
The data suggest that ATM and , even better , ATR inhibition is a useful strategy in sensitizing Cancercancer cells to temozolomide and presumably also other anticancer drugs .
23969938
PURPOSE : To evaluate the clinical activity of sequential therapy with sorafenib and sunitinib in FMS like tyrosine kinase 3 ( FLT3 )-internal tandem duplication ( CancerITD )-positive acute myelogenous leukemia ( AML ) and monitor the emergence of secondary FLT3 tyrosine kinase domain ( TKD ) mutations during treatment .
23982599
Afatinib , an irreversible inhibitor of the ErbB family of tyrosine kinases , is under development with Boehringer Ingelheim for the once-daily , oral treatment of Cancercancer .
23982599
Oral afatinib ( Gilotrif ( TM ) ) has been approved in the US for the first-line treatment of patients with Cancermetastatic non-small-cell lung cancer ( NSCLC ) who have tumours with EGFR exon 19 deletions or exon 21 ( L858R ) substitution mutations as detected by a US FDA approved test .
23982599
Oral afatinib ( Gilotrif ( TM ) ) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer ( NSCLC ) who have Cancertumours with EGFR exon 19 deletions or exon 21 ( L858R ) substitution mutations as detected by a US FDA approved test .
23988873
The fluoropyrimidines are the mainstay chemotherapeutic agents for the treatment of many types of Cancercancers .
23988873
Detoxifying metabolism of fluoropyrimidines requires dihydropyrimidine dehydrogenase ( DPD , encoded by the DPYD gene ) , and reduced or absent activity of this enzyme can result in severe , and sometimes fatal , Diseasetoxicity .
23989949
In patients with Canceradvanced transitional cell carcinoma ( TCC ) treated with the mTOR inhibitor everolimus , PTEN loss was , however , associated with resistance to treatment .
23989949
METHODS : CancerTransitional cell carcinoma specimens , human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors .
23989949
METHODS : Transitional cell carcinoma specimens , Cancerhuman bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors .
23989949
RESULTS : CancerTransitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation .
23989949
Moreover , CancerPTEN deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN , and rapamycin strikingly induced Akt activation in the absence of functional PTEN .
23989949
These data support the use of both PI3K and mTOR inhibitors to treat Cancerurothelial carcinoma , in particular in the absence of functional PTEN .
24013721
CancerMantle cell lymphoma ( MCL ) is a B-cell malignancy characterized by a poor response to treatment and prognosis .
24013721
Mantle cell lymphoma ( MCL ) is a CancerB-cell malignancy characterized by a poor response to treatment and prognosis .
24013721
Constitutive activation of different signaling pathways in subsets of MCLs , through genetic and/or nongenetic alterations , endows Cancertumor cells with enhanced proliferation and reduced apoptosis .
24013721
The canonical Wnt pathway ( beta-catenin and TCF-LEF ) , implicated in the pathogenesis of Cancernumerous cancers , is constitutively active in half of MCLs .
24013721
Here , we show that ZEB1 , a transcription factor better known for promoting Cancermetastasis in carcinomas , is expressed in primary MCLs with active Wnt signaling .
24013721
Here , we show that ZEB1 , a transcription factor better known for promoting metastasis in Cancercarcinomas , is expressed in primary MCLs with active Wnt signaling .
24013721
Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells , and , importantly , Cancertumor growth in mouse xenograft models .
24013721
These results identify ZEB1 in MCL where it promotes cell proliferation , enhanced Cancertumor growth and a differential response to chemotherapy drugs .
24013721
ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this Cancerlymphoma .
24035188
OBJECTIVES : Although T790M mutation is considered to be the major mechanism of acquired resistance to epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors ( TKIs ) in patients with Cancernon small cell lung cancer ( NSCLC ) , its clinical implication remains undetermined .
24035188
METHODS : CancerPost-progression tumor specimens were prospectively collected for T790M mutation analysis in NSCLC patients with acquired resistance to initial EGFR TKIs .
24035188
There was no difference in the pattern of Diseasedisease progression , progression-free survival for initial TKIs ( 12.8 and 11.3 months ) , post-progression survival ( 14.7 and 14.1 months ) , or overall survival ( 43.5 and 36.8 months ) in patients with and without T790M .
24035188
Although T790M had no prognostic or predictive role in the present study , further research is necessary to identify patients with CancerT790M-mutant tumors who might benefit from newly developed T790M specific TKIs .
24039832
Activating epidermal growth factor receptor ( EGFR ) mutations are recognized biomarkers for patients with Cancermetastatic non small cell lung cancer ( NSCLC ) treated with EGFR tyrosine kinase inhibitors ( TKIs ) .
24039832
Previous studies on Cancertumor EGFR protein levels and EGFR gene copy number revealed inconsistent results .
24039832
We used exon arrays and clinical samples from a previous trial ( SAKK19/05 ) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response : EGFR , CancerV-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) and vascular endothelial growth factor ( VEGFA ) .
24039832
The overexpression of EGFR exon 18 in Cancertumor was significantly associated with tumor shrinkage , independently of EGFR mutation status .
24039832
The overexpression of EGFR exon 18 in tumor was significantly associated with Cancertumor shrinkage , independently of EGFR mutation status .
24039832
Based on these results , we propose a new model of EGFR testing in Cancertumor and blood .
24065731
Patients with Cancernon small cell lung cancer ( NSCLC ) with activating EGF receptor ( EGFR ) mutations initially respond to first generation reversible EGFR tyrosine kinase inhibitors .
24065731
Oral administration of CO-1686 as single agent induces Cancertumor regression in EGFR mutated NSCLC tumor xenograft and transgenic models .
24065731
Oral administration of CO-1686 as single agent induces tumor regression in EGFR mutated CancerNSCLC tumor xenograft and transgenic models .
24065731
CO-1686 is the fi rst drug of its class in clinical development for the treatment of T790M positive NSCLC , potentially offering potent inhibition of mutant EGFR while avoiding the Diseaseon-target toxicity observed with inhibition of the WT EGFR .
24088382
INTRODUCTION : Activation of the PI3K and AKT pathway is a common phenomenon in Cancercancer due to multiple mechanisms , including mutation of PI3KCA , loss or mutation of PTEN , or over-expression of receptor tyrosine kinases .
24088382
CASE PREPARATION : To further elucidate the correlation between AZD5363 response and genetic alterations in Cancergastric cancer ( GC ) and identify GC patients with both PI3KCA mutations and PTEN loss , we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients .
24088382
CASE PREPARATION : To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer ( GC ) and identify GC patients with both PI3KCA mutations and PTEN loss , we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in Cancertumor samples from a cohort of Chinese GC patients .
24088382
DiseaseDisease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7 % ( 4/150 ) and 23 % ( 14/61 ) of Chinese GC patients respectively .
24088390
BACKGROUND : Several lines of evidence indicate that Sirt1 , a class III histone deacetylase ( HDAC ) is implicated in the initiation and progression of Cancermalignancies and thus gained attraction as druggable target .
24088390
Since data on the role of Sirt1 in Cancerpancreatic ductal adenocarcinoma ( PDAC ) are sparse , we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro .
24088390
Furthermore , we investigated the impact of overexpression and small molecule inhibition on Sirt1 in Cancerpancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition .
24088390
SIRT1 expression was significantly higher in poorly differentiated Cancercarcinomas .
24088390
Accordingly , overexpression of Sirt1 led to increased cell viability , while small molecule inhibition led to a growth arrest in Cancerpancreatic cancer cells and impaired cell survival .
24088390
CONCLUSIONS : Sirt1 is an independent prognosticator in PDACs and plays an important role in Cancerpancreatic cancer cell growth , which can be levered out by small molecule inhibition .
24097869
EXPERIMENTAL DESIGN : We use a NAMPT inhibitor , GNE-617 , to evaluate nicotinic acid rescue status in a panel of more than 400 Cancercancer cell lines .
24097869
Finally , we develop immunohistochemical ( IHC ) and DNA methylation assays and evaluate Cancercancer tissue for prevalence of the biomarker across indications .
24097869
We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in Cancercancer cells , and NAPRT1 methylation is predictive of rescue status in cancer cell lines .
24097869
We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells , and NAPRT1 methylation is predictive of rescue status in Cancercancer cell lines .
24097869
Bisulfite next generation sequencing mapping of the NAPRT1 promoter identified Cancertumor specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation specific PCR ( QMSP ) assay suitable for use on archival formalin fixed paraffin embedded tumor tissue .
24097869
Bisulfite next generation sequencing mapping of the NAPRT1 promoter identified tumor specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation specific PCR ( QMSP ) assay suitable for use on archival formalin fixed Cancerparaffin embedded tumor tissue .
24097869
CONCLUSIONS : CancerTumor specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways , resulting in synthetic lethality with the coadministration of a NAMPT inhibitor .
24097869
NAPRT1 expression is lost due to promoter hypermethylation in Cancermost cancer types evaluated at frequencies ranging from 5 % to 65 % .
24097869
NAPRT1 specific immunohistochemical or DNA methylation assays can be used on Cancerarchival formalin paraffin embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid .
24098545
For each study , AdverseOutcomerelative risks and 95 % confidence intervals were extracted and pooled with a fixed and random effects model .
24098545
ELIGIBILITY CRITERIA FOR SELECTING STUDIES : Criteria for inclusion were studies reporting Cancerbreast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene .
24098545
RESULTS : Twenty-five studies of 13,629 individuals were identified , of which 22 investigated the association of CYP2D6 genotype with outcomes in Cancerbreast cancer women all receiving tamoxifen treatment ( " treatment-only " design ) .
24098545
In analysis of treatment-only studies , the AdverseOutcomerelative risk ( RR ) of all-cause mortality ( > 307 events in 4,936 patients ) for carriers of a CYP2D6 reduced function allele was 1.11 ( 95 % confidence interval ( CI ) : 0.94 to 1.31 ) compared to individuals with normal and increased function CYP2D6 alleles .
24098545
In analysis of treatment-only studies , the relative risk ( RR ) of all-cause AdverseOutcomemortality ( > 307 events in 4,936 patients ) for carriers of a CYP2D6 reduced function allele was 1.11 ( 95 % confidence interval ( CI ) : 0.94 to 1.31 ) compared to individuals with normal and increased function CYP2D6 alleles .
24098545
When we investigated a composite outcome including all-cause AdverseOutcomemortality and surrogate endpoints for overall survival ( > 307 events in 6,721 patients ) , carriers of a CYP2D6 reduced function allele had a RR of 1.27 ( 95 % CI : 1.11 to 1.45 ) .
24112705
Resistance to the BRAF inhibitor vemurafenib poses a significant problem for the treatment of CancerBRAFV600E positive melanomas .
24112705
Our results identify a novel vemurafenib resistant mutant and provide insights into the treatment for Cancermelanomas bearing this mutation .
24122810
Cholangiocarcinoma is an Cancerintractable cancer , with limited therapeutic options , in which the molecular mechanisms underlying tumor development remain poorly understood .
24122810
Cholangiocarcinoma is an intractable cancer , with limited therapeutic options , in which the molecular mechanisms underlying Cancertumor development remain poorly understood .
24122810
Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined Cancercancers might lead to improvements in the outcome of patients .
24122810
We performed massively parallel whole transcriptome sequencing in eight specimens from Cancercholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes , FGFR2-AHCYL1 and FGFR2-BICC1 .
24122810
In reverse-transcriptase polymerase chain reaction ( RT-PCR ) screening , the FGFR2 fusion was detected in nine patients with Cancercholangiocarcinoma ( 9/102 ) , exclusively in the intrahepatic subtype ( 9/66 , 13.6 % ) , rarely in colorectal ( 1/149 ) and hepatocellular carcinoma ( 1/96 ) , and none in gastric cancer ( 0/212 ) .
24122810
In reverse-transcriptase polymerase chain reaction ( RT-PCR ) screening , the FGFR2 fusion was detected in nine patients with cholangiocarcinoma ( 9/102 ) , exclusively in the intrahepatic subtype ( 9/66 , 13.6 % ) , rarely in colorectal ( 1/149 ) and Cancerhepatocellular carcinoma ( 1/96 ) , and none in gastric cancer ( 0/212 ) .
24122810
In reverse-transcriptase polymerase chain reaction ( RT-PCR ) screening , the FGFR2 fusion was detected in nine patients with cholangiocarcinoma ( 9/102 ) , exclusively in the intrahepatic subtype ( 9/66 , 13.6 % ) , rarely in colorectal ( 1/149 ) and hepatocellular carcinoma ( 1/96 ) , and none in Cancergastric cancer ( 0/212 ) .
24122810
Treatment with the fibroblast growth factor receptor ( FGFR ) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation.CONCLUSION : FGFR2 fusions occur in 13.6 % of Cancerintrahepatic cholangiocarcinoma .
24122810
The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of Cancercholangiocarcinoma and suggest a new therapeutic approach to the disease .
24122810
The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the Diseasedisease .
24132921
Dysregulation of PDGFRA has been reported in Cancermany cancers .
24132921
However , PDGFRA mutations in Cancermelanomas have not been well studied .
24132921
We analyzed the genetic mutations of PDGFRA in Chinese patients with Cancermelanoma and determined the inhibitory potency of TKIs , such as imatinib and crenolanib , on mutant PDGFRA .
24132921
EXPERIMENTAL DESIGN : Of note , 351 Cancermelanoma tissue samples were examined for genetic mutations in exons 12 , 14 , and 18 of PDGFRA .
24132921
RESULTS : PDGFRA mutations were observed in 4.6 % ( 16 of 351 ) of Cancermelanomas , and these mutations were mainly detected in acral and mucosal melanomas .
24132921
RESULTS : PDGFRA mutations were observed in 4.6 % ( 16 of 351 ) of melanomas , and these mutations were mainly detected in acral and Cancermucosal melanomas .
24132921
The genetic mutations of PDGFRA were unrelated to the age , thickness , and ulceration status of Cancerprimary melanomas .
24132921
CONCLUSIONS : PDGFRA mutations are detected in a small population of Cancermelanoma patients .
24132921
Our study suggests that patients with Cancermelanoma harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment .
24135816
BACKGROUND and AIMS : Resembling a potential therapeutic drug target , fibroblast growth factor receptor 1 ( FGFR1 ) amplification and expression was assessed in 515 Cancerhuman colorectal cancer ( CRC ) tissue samples , lymph node metastases and CRC cell lines .
24135816
92/94 lymph node metastases presented the same amplification status as the Cancerprimary tumor .
24135816
Of 99 investigated Cancertumors , 18 revealed membranous activated pFGFR1 protein .
24137399
Germline mutations in the Cancerhuman breast cancer genes BRCA1 and BRCA2 account for a substantial proportion of familial , early-onset breast and ovarian cancers .
24137399
Germline mutations in the human breast cancer genes BRCA1 and BRCA2 account for a substantial proportion of familial , early-onset breast and Cancerovarian cancers .
24137399
The present study reports a Diseasenovel disease causing BRCA1 mutation , nucleotide 3020insCT/c .2901 insCT , in a 55-year-old Spanish female with breast and ovarian cancer .
24137399
The present study reports a novel disease causing BRCA1 mutation , nucleotide 3020insCT/c .2901 insCT , in a 55-year-old Spanish female with breast and Cancerovarian cancer .
24137399
To the best of our knowledge , this mutation has not been previously described in the CancerBreast Cancer Information Core ( BIC ) database or the published literature .
24140933
CancerUveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung .
24140933
Uveal melanoma is the most Cancercommon primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung .
24140933
Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the Cancerprimary tumors will develop fatal metastatic disease to the liver and the lung .
24140933
Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop Diseasefatal metastatic disease to the liver and the lung .
24140933
Crizotinib , an inhibitor of c-Met , Canceranaplastic lymphoma kinase ( ALK ) , and ROS1 , inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and tumor tissue .
24140933
Crizotinib , an inhibitor of c-Met , anaplastic lymphoma kinase ( ALK ) , and ROS1 , inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in Canceruveal melanoma cells and tumor tissue .
24140933
Crizotinib , an inhibitor of c-Met , anaplastic lymphoma kinase ( ALK ) , and ROS1 , inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and Cancertumor tissue .
24140933
Consequently , migration of Canceruveal melanoma cells was suppressed in vitro at a concentration associated with the specific inhibition of c-Met phosphorylation .
24140933
Therefore , we developed a Canceruveal melanoma metastatic mouse model with EGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis .
24140933
Therefore , we developed a uveal melanoma metastatic mouse model with CancerEGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis .
24140933
Therefore , we developed a uveal melanoma metastatic mouse model with EGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on Cancermetastasis .
24140933
In this model , there was development of Cancermelanoma within the eye and also metastases to the liver and lung at 7 weeks after the initial transplantation .
24140933
These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit Cancermetastasis of uveal melanoma from forming , suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease .
24140933
These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of Canceruveal melanoma from forming , suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease .
24140933
These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming , suggesting crizotinib as a potential adjuvant therapy for patients with Cancerprimary uveal melanoma who are at high risk for the development of metastatic disease .
24140933
These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming , suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at AdverseOutcomehigh risk for the development of metastatic disease .
24140933
These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming , suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of Diseasemetastatic disease .
24146218
BACKGROUND : HER2 is an established therapeutic target in breast and Cancergastric cancers .
24146218
The role of HER2 in Cancerrectal cancer is unclear , as conflicting data on the prevalence of HER2 expression in this disease have been reported .
24146218
The role of HER2 in rectal cancer is unclear , as conflicting data on the prevalence of HER2 expression in this Diseasedisease have been reported .
24146218
We evaluated the prevalence of HER2 and its impact on the outcome of Cancerhigh-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT +/-cetuximab in the EXPERT-C trial .
24146218
PATIENTS AND METHODS : Eligible patients with Canceravailable tumour tissue for HER2 analysis were included .
24146218
Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for Cancergastric cancer .
24146218
CONCLUSIONS : Based on the low prevalence of expression as recorded in the EXPERT-C trial , HER2 does not appear to represent a useful therapeutic target in Cancerhigh-risk rectal cancer .
24146218
However , the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in Canceranti-EGFR refractory metastatic colorectal cancer ( CRC ) warrants further investigation .
24162815
We identified new gene fusions in patients with Cancerlung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor ( TRKA protein ) .
24162815
CancerTumor samples from 3 of 91 patients with lung cancer ( 3.3 % ) without known oncogenic alterations assayed by next generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions .
24162815
Tumor samples from 3 of 91 patients with Cancerlung cancer ( 3.3 % ) without known oncogenic alterations assayed by next generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions .
24166148
BACKGROUND : Targeting the phosphatidylinositol 3-kinase ( PI3K )/AKT/mammalian target of rapamycin ( mTOR ) pathway is of increasing interest as a therapeutic strategy in Cancermany tumors .
24166148
The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with Cancermetastatic endometrial cancer .
24166148
METHODS : CancerArchival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors : IND160A and IND160B ( temsirolimus ) and IND192 ( ridaforolimus ) .
24166148
METHODS : Archival tumor samples were collected from 94 women with recurrent or Cancermetastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors : IND160A and IND160B ( temsirolimus ) and IND192 ( ridaforolimus ) .
24166148
RESULTS : Mutations were found in 32 of 73 analyzed Cancertumors , PIK3CA ( 21 patients ) was the most common mutated gene .
24166148
Co-mutations were seen in 8 Cancertumors , most frequently KRAS and PIK3CA ( 4 cases ) .
24166148
Restriction and enrichment of study entry , especially based on Cancerarchival tumor tissue , should be undertaken with caution in trials using these agents .
24167368
Endocrine resistance is a significant problem in Cancerbreast cancer treatment .
24167368
In our work , AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen treated Cancerpostmenopausal breast cancer patients .
24167368
Our results showed inversed association of AGR2 mRNA levels with primary treatment response ( P = 0.0011 ) and progression-free survival ( P = 0.0366 ) in 61 CancerER positive breast carcinomas .
24167368
From this perspective , AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in Cancerpostmenopausal ER positive breast cancer patients .
24178622
PURPOSE : The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway , activated in 70 % to 80 % of patients with Canceracute myelogenous leukemia ( AML ) , is unknown .
24178622
CancerLeukemia cells were analyzed for extracellular signal regulated kinase ( ERK ) and mTOR phosphorylation .
24178622
RESULTS : DiseaseCommon drug related toxicities were grade 1-2 diarrhea , fatigue , nausea , vomiting , and skin rash .
24178622
A single-nucleotide polymorphism ( SNP ) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response and Diseasestable disease compared with nonresponders ( 60 % vs. 23 % ; P = 0.027 ) .
24178622
However , given its Diseasefavorable toxicity profile , combination with drugs that target other signaling pathways in AML should be considered .
24185510
CancerBreast cancer is the most prevalent cancer in women , and over two-thirds of cases express estrogen receptor-alpha ( ER-alpha , encoded by ESR1 ) .
24185510
Breast cancer is the most Cancerprevalent cancer in women , and over two-thirds of cases express estrogen receptor-alpha ( ER-alpha , encoded by ESR1 ) .
24185510
Through a prospective clinical sequencing program for Canceradvanced cancers , we enrolled 11 patients with ER positive metastatic breast cancer .
24185510
Through a prospective clinical sequencing program for advanced cancers , we enrolled 11 patients with CancerER positive metastatic breast cancer .
24185510
A survey of The CancerCancer Genome Atlas ( TCGA ) identified four endometrial cancers with similar mutations of ESR1 .
24185510
A survey of The Cancer Genome Atlas ( TCGA ) identified four Cancerendometrial cancers with similar mutations of ESR1 .
24185510
Taken together , these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in Cancerbreast cancer therapy .
24185512
Seventy percent of Cancerbreast cancers express estrogen receptor ( ER ) , and most of these are sensitive to ER inhibition .
24185512
However , Cancermany such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting .
24185512
We conducted a comprehensive genetic analysis of two independent cohorts of Cancermetastatic ER positive breast tumors and identified mutations in ESR1 affecting the ligand binding domain ( LBD ) in 14 of 80 cases .
24192513
The initial radiotherapy of a 73 years old Caucasian male patient with Canceradvanced squamous cell lung carcinoma was terminated due to severe pericarditis .
24192513
The initial radiotherapy of a 73 years old Caucasian male patient with advanced squamous cell lung carcinoma was terminated due to Diseasesevere pericarditis .
24192513
Subsequently , the Cancertumor sample was analyzed for possible targets with comprehensive molecular diagnostics .
24192513
The kinase inhibitor crizotinib is already in clinical use for the treatment of CancerALK positive non small cell lung cancers , but it is also known to be a potent c-MET inhibitor .
24192513
C-MET expression is associated with AdverseOutcomepoor prognosis and resistance to EGFR inhibitors .
24192513
This case may indicate that c-MET tyrosine kinase inhibitors can be an effective targeted treatment option for Cancersquamous cell carcinoma patients , and future clinical trials should be expanded for this patient group as well .
24236021
BCR-ABL kinase domain inhibition can be used to treat Cancerchronic myeloid leukemia .
24239278
OBJECTIVES : Head and Cancerneck squamous cell carcinomas ( HNSCCs ) are characterized by marked heterogeneity in their biological behavior and response to treatment .
24239278
MATERIALS AND METHODS : The expression of EGFR , p53 , Cyclin D1 , p16 , p21 , p27 , p-AKT , HIF-1alpha , Caspase 3 and BCL2 was analyzed by immunohistochemistry in 41 primary laryngeal and Cancerhypopharyngeal squamous cell carcinomas of patients that received induction chemotherapy ( cisplatin and 5-fluorouracil ) as part of their treatment .
24240112
PURPOSE : Hallmarks of germline BRCA1/2 associated Cancerovarian carcinomas include chemosensitivity and improved survival .
24240112
EXPERIMENTAL DESIGN : Using targeted capture and massively parallel genomic sequencing , we assessed 390 Cancerovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes , including BRCA1 , BRCA2 , and 11 other genes in the homologous recombination pathway .
24240112
RESULTS : Thirty-one percent of Cancerovarian carcinomas had a deleterious germline ( 24 % ) and/or somatic ( 9 % ) mutation in one or more of the 13 homologous recombination genes : BRCA1 , BRCA2 , ATM , BARD1 , BRIP1 , CHEK1 , CHEK2 , FAM175A , MRE11A , NBN , PALB2 , RAD51C , and RAD51D .
24240112
CancerNonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas ( 28 % vs. 31 % , P = 0.6 ) , including clear cell , endometrioid , and carcinosarcoma .
24240112
Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to Cancerserous carcinomas ( 28 % vs. 31 % , P = 0.6 ) , including clear cell , endometrioid , and carcinosarcoma .
24240112
Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas ( 28 % vs. 31 % , P = 0.6 ) , including clear cell , endometrioid , and Cancercarcinosarcoma .
24240112
CONCLUSIONS : Germline or somatic mutations in homologous recombination genes are present in almost one third of Cancerovarian carcinomas , including both serous and nonserous histologies .
24240112
The similar rate of homologous recombination mutations in Cancernonserous carcinomas supports their inclusion in PARP inhibitor clinical trials .
24240700
Small-molecule inhibitors of PARP1/2 , such as olaparib , have been proposed to serve as a synthetic lethal therapy for Cancercancers that harbor BRCA1 or BRCA2 mutations .
24240700
In support of this hypothesis , the set of identified genes included known determinants of olaparib sensitivity , such as BRCA1 , RAD51 , and Fanconi 's Diseaseanemia susceptibility genes .
24240700
Notably , integration of the list of candidate sensitivity genes with data from Cancertumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity .
24240700
In models of Cancerhigh-grade serous ovarian cancer ( HGS-OVCa ) , CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition , suppression of DNA repair via homologous recombination , and reduced expression of BRCA1 .
24253377
In this study , we explored the effects of circadian control on the pivot cell growth regulatory mTOR , the activity of which is deregulated in Cancertumor cells compared with normal cells .
24253377
Specifically , we investigated whether the antitumor effect of an mTOR inhibitor could be improved by changing its dosing schedule in CancerRenCa tumor bearing mice .
24253377
Active , phosphorylated mTOR displayed a 24-hour rhythm , and levels of total mTOR protein ( but not mRNA ) also showed a circadian rhythm in CancerRenCa tumor masses .
24253377
Notably , administration of the mTOR inhibitor everolimus during periods of elevated mTOR improved survival in Cancertumor bearing mice .
24256029
The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene ( TOP1 ) copy number and objective response following irinotecan treatment in patients with Cancermetastatic colorectal cancer .
24256029
MATERIALS AND METHODS : Formalin fixed , Cancerparaffin embedded tumor samples from 78 patients , who received irinotecan monotherapy in second line , were included .
24256029
CONCLUSIONS : Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in Cancerlarger tumor material , preferably in a randomized setting , is highly warranted .
24265152
BRAF inhibitor ( BRAFi ) therapy leads to Cancerremarkable anti melanoma responses , but the initial tumor shrinkage is commonly incomplete , providing a nidus for subsequent disease progression .
24265152
BRAF inhibitor ( BRAFi ) therapy leads to remarkable anti melanoma responses , but the Cancerinitial tumor shrinkage is commonly incomplete , providing a nidus for subsequent disease progression .
24265152
BRAF inhibitor ( BRAFi ) therapy leads to remarkable anti melanoma responses , but the initial tumor shrinkage is commonly incomplete , providing a nidus for Diseasesubsequent disease progression .
24265152
We show here that BRAFi ( or BRAFi + MEKi ) therapy in patients frequently led to rebound phosphorylated AKT ( p-AKT ) levels in their Cancermelanomas early on-treatment .
24265152
Thus , adaptive or genetic upregulation of AKT critically participates in Cancermelanoma survival during BRAFi therapy .
24277854
Wnt signaling is one of the key oncogenic pathways in Cancermultiple cancers , and targeting this pathway is an attractive therapeutic approach .
24277854
LGK974 is potent and efficacious in Cancermultiple tumor models at well tolerated doses in vivo , including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model ( HN30 ) .
24277854
LGK974 is potent and efficacious in multiple tumor models at well tolerated doses in vivo , including murine and Cancerrat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model ( HN30 ) .
24277854
LGK974 is potent and efficacious in multiple tumor models at well tolerated doses in vivo , including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and Cancerneck squamous cell carcinoma model ( HN30 ) .
24277854
We also show that head and Cancerneck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974 .
24277854
Together , these findings provide both a strategy and tools for targeting Wnt driven Cancercancers through the inhibition of PORCN .
24296758
Activated Canceranaplastic lymphoma kinase ( ALK ) and ROS1 tyrosine kinases , through gene fusions , have been found in lung adenocarcinomas and are highly sensitive to selective kinase inhibitors .
24296758
Activated anaplastic lymphoma kinase ( ALK ) and ROS1 tyrosine kinases , through gene fusions , have been found in Cancerlung adenocarcinomas and are highly sensitive to selective kinase inhibitors .
24296758
This study aimed at identifying the presence of these rearrangements in Cancerhuman colorectal adenocarcinoma specimens using a 4-target , 4-color break-apart FISH assay to simultaneously determine the genomic status of ALK and ROS1 .
24296758
Among the Cancerclinical colorectal cancer specimens analyzed , rearrangement positive cases for both ALK and ROS1 were observed .
24296758
Despite the additional oncogenic events and Cancertumor heterogeneity observed , elucidation of the first cases of ROS1 rearrangements and confirmation of ALK rearrangements support further evaluation of these genomic fusions as potential therapeutic targets in colorectal cancer.IMPLICATIONS : ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection .
24296758
Despite the additional oncogenic events and tumor heterogeneity observed , elucidation of the first cases of ROS1 rearrangements and confirmation of ALK rearrangements support further evaluation of these genomic fusions as potential therapeutic targets in colorectal cancer.IMPLICATIONS : ROS1 and ALK fusions occur in Cancercolorectal cancer and may have substantial impact in therapy selection .
24297342
The overall survival rate and prognosis of patients with Cancerlaryngeal cancer are not optimistic despite advances in therapeutic techniques .
24297342
The human gene PTPN11 encoding a non receptor protein tyrosine phosphatase , Src homology phosphotyrosine phosphatase 2 ( SHP2 ) , is a well documented proto-oncogene in Cancervarious malignancies .
24297342
This study investigated the role of SHP2 expression and associated clinical manifestations in Cancerlaryngeal cancer using a tissue microarray of 112 pairs of laryngeal cancer samples and corresponding adjacent normal mucosae .
24297342
This study investigated the role of SHP2 expression and associated clinical manifestations in laryngeal cancer using a tissue microarray of 112 pairs of Cancerlaryngeal cancer samples and corresponding adjacent normal mucosae .
24297342
SHP2 expression increased in Cancerlaryngeal cancer , and this result was associated with the poor survival rate of laryngeal cancer patients .
24297342
SHP2 expression increased in laryngeal cancer , and this result was associated with the poor survival rate of Cancerlaryngeal cancer patients .
24297342
Moreover , increased SHP2 expression remarkably promoted the growth of Cancerlaryngeal cancer cells in vitro and tumorigenicity of laryngeal cancer cells in vivo .
24297342
Moreover , increased SHP2 expression remarkably promoted the growth of laryngeal cancer cells in vitro and tumorigenicity of Cancerlaryngeal cancer cells in vivo .
24297342
The Ras/Raf/Mek/Erk pathway was also found to be involved in the SHP2 induced growth of Cancerlaryngeal cancer cells .
24297342
Overall , our findings indicated that SHP2 plays an important role in Cancerlaryngeal cancer tumorigenesis and that its expression is negatively correlated with the prognosis of patients .
24297342
Thus , SHP2 may be a promising combinational therapeutic target for treatment of Cancerlaryngeal cancer .
24297342
The interference of SHP2 expression can serve as a novel strategy for Cancerlaryngeal cancer treatment .
24327581
We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in Cancerrecurrent high-grade glioma treated with bevacizumab .
24327581
CONCLUSION : In patients with Cancerrecurrent high-grade glioma treated with bevacizumab , but not with cytotoxic agent , high MMP2 plasma levels are associated with prolonged tumor control and survival .
24327581
CONCLUSION : In patients with recurrent high-grade glioma treated with bevacizumab , but not with cytotoxic agent , high MMP2 plasma levels are associated with Cancerprolonged tumor control and survival .
24333121
The incidence of mutations in isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) in de novo Canceracute myeloid leukemia ( AML ) is approximately 20 % .
24333121
These mutations result in distinct metabolic characteristics including dependency of Cancercancer cells on glutamine as the main source for alpha-ketoglutarate , which is consumed by leukemia cells to produce a cancer derived metabolite , 2-hydroxyglutarate .
24333121
These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for alpha-ketoglutarate , which is consumed by Cancerleukemia cells to produce a cancer derived metabolite , 2-hydroxyglutarate .
24333121
These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for alpha-ketoglutarate , which is consumed by leukemia cells to produce a Cancercancer derived metabolite , 2-hydroxyglutarate .
24333121
This study lays the groundwork for strategies to target a specific subtype of AML metabolically with IDH mutations with a unique reprogramming of intermediary metabolism that culminates in glutamine dependency of Cancercancer cells for survival .
24335962
CancerTriple negative breast cancer ( TNBC ) is currently the only major breast tumor subtype without effective targeted therapy and , as a consequence , in general has a poor outcome .
24335962
Triple negative breast cancer ( TNBC ) is currently the Canceronly major breast tumor subtype without effective targeted therapy and , as a consequence , in general has a poor outcome .
24335962
Triple negative breast cancer ( TNBC ) is currently the only major breast tumor subtype without effective targeted therapy and , as a consequence , in general has a AdverseOutcomepoor outcome .
24335962
To identify new therapeutic targets in TNBC , we performed a short hairpin RNA ( shRNA ) screen for protein kinases commonly amplified and overexpressed in Cancerbreast cancer .
24335962
These results imply that Akt3 has a specific function in TNBCs ; thus , its therapeutic targeting may provide a new treatment option for this Cancertumor subtype .
24345920
PURPOSE : Recurrent " driver " mutations at specific loci in BRAF , NRAS , KIT , GNAQ , and GNA11 define clinically relevant molecular subsets of Cancermelanoma , but more than 30 % are " pan negative " for these recurrent mutations .
24345920
We sought to identify additional potential drivers in " pan negative " Cancermelanoma .
24345920
EXPERIMENTAL DESIGN : Using a targeted next generation sequencing ( NGS ) assay ( FoundationOne ( TM ) ) and targeted RNA sequencing , we identified a novel PAPSS1-BRAF fusion in a " pan negative " Cancermelanoma .
24345920
We then analyzed NGS data from 51 Canceradditional melanomas genotyped by FoundationOne ( TM ) , as well as melanoma RNA , whole-genome and whole-exome sequencing data in The Cancer Genome Atlas ( TCGA ) , to determine the potential frequency of BRAF fusions in melanoma .
24345920
We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne ( TM ) , as well as Cancermelanoma RNA , whole-genome and whole-exome sequencing data in The Cancer Genome Atlas ( TCGA ) , to determine the potential frequency of BRAF fusions in melanoma .
24345920
We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne ( TM ) , as well as melanoma RNA , whole-genome and whole-exome sequencing data in The CancerCancer Genome Atlas ( TCGA ) , to determine the potential frequency of BRAF fusions in melanoma .
24345920
We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne ( TM ) , as well as melanoma RNA , whole-genome and whole-exome sequencing data in The Cancer Genome Atlas ( TCGA ) , to determine the potential frequency of BRAF fusions in Cancermelanoma .
24345920
NGS data analysis of 51 Canceradditional melanomas revealed a second BRAF fusion ( TRIM24-BRAF ) in a " pan negative " sample ; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive .
24345920
Through Cancermining TCGA skin cutaneous melanoma dataset , we further identified two potential BRAF fusions in another 49 " pan negative " cases .
24345920
CONCLUSIONS : BRAF fusions define a new molecular subset of Cancermelanoma , potentially comprising 4 % to 8 % of " pan negative " cases .
24354346
CONTEXT : An activating mutation in the gene BRAF has been correlated with poorer prognosis and more aggressive clinical course in Cancerpapillary thyroid carcinoma ( PTC ) .
24354346
We therefore hypothesized that the good prognosis , high 5-year disease-free rate and high survival rate of patients with Cancerless aggressive papillary thyroid microcarcinoma ( pT1aNo-x ) would be associated with a lower incidence of the BRAF ( V600E ) mutation .
24354346
OBJECTIVES : To evaluate the frequency of the activating mutation BRAF ( V600E ) in Cancerlow-risk papillary thyroid microcarcinoma ( pT1aNo-x at the moment of diagnosis ) and the association of the mutation with the clinical outcome in a retrospective analysis .
24354346
Genotyping was performed on DNA extracted from Cancerthyroid tumour tissue using direct capillary sequencing , and allele specific amplification PCR was used to resolve equivocal results .
24354346
Retrospective analysis of the clinical course of PTC was then correlated with BRAF status in the Cancerprimary tumour tissue .
24354346
CONCLUSIONS : The presence of the activating BRAF ( V ) ( 600E ) mutation in a significant percentage of Cancerpapillary thyroid microcarcinoma indicates that further analyses are required to verify its usefulness as a predictor of clinical outcome in PTC .
24354346
In this study , there was no correlation between BRAF positive primary focus of Cancerpapillary microcarcinoma and more aggressive or recurrent disease .
24354346
In this study , there was no correlation between BRAF positive primary focus of papillary microcarcinoma and more aggressive or Diseaserecurrent disease .
24356815
NVP-BEZ235 is a newly developed dual PI3K and mTOR inhibitor , being tested in multiple clinical trials , including Cancerbreast cancer .
24356815
NVP-BEZ235 selectively induces cell growth inhibition in a subset , but not all , Cancerbreast cancer cell lines .
24356815
However , it remains a challenge to distinguish between sensitive and Cancerresistant tumors , particularly in the pretreatment setting .
24356815
Here , we used ten Cancerbreast cancer cell lines to compare NVP-BEZ235 sensitivity and in the context of androgen receptor ( AR ) activation during NVP-BEZ235 treatment .
24356815
We also used female SCID mice bearing Cancerbreast tumor xenografts to investigate the beneficial effect of dihydrotestosterone and NVP-BEZ 235 combination treatment compared with each alone .
24356815
We found that CancerAR positive breast cancer cell lines are much more sensitive to NVP-BEZ235 compared with AR negative cells , regardless of PTEN or PI3KCA status .
24356815
DHT and NVP-BEZ 235 combination not only resulted in a more significant growth inhibition than either drug alone , but also achieved Cancertumor regression and complete responses for AR ( + )/ER ( + ) tumors .
24356815
DHT and NVP-BEZ 235 combination not only resulted in a more significant growth inhibition than either drug alone , but also achieved tumor regression and complete responses for AR ( + )/ER ( + ) Cancertumors .
24356815
AR induction could add benefit during NVP-BEZ235 treatment in patients , especially with AR ( + )/ER ( + ) Cancerbreast carcinomas .
24366361
CancerChildhood BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia ( BCP-ALL ) has an unfavorable outcome and shows high frequency of IKZF1 deletions .
24366361
The prognostic value of IKZF1 deletions was evaluated in 2 cohorts of BCR-ABL1-positive BCP-ALL patients , before tyrosine kinase inhibitors ( pre-TKI ) and after introduction of imatinib ( in the European Study for CancerPhiladelphia-Acute Lymphoblastic Leukemia [ EsPhALL ] ) .
24367492
Most women with estrogen receptor expressing Cancerbreast cancers receiving anti-estrogens such as tamoxifen may not need or benefit from them .
24367492
Besides the estrogen receptor , there are no predictive biomarkers to help Cancerselect breast cancer patients for tamoxifen treatment .
24367492
We validated the predictive value of these biomarkers in the MA .12 randomized study of adjuvant tamoxifen vs. placebo in Cancerhigh-risk premenopausal early breast cancer .
24367492
Premenopausal women with node-positive and Cancerhigh-risk node negative early breast cancer received standard adjuvant chemotherapy and then were randomized to tamoxifen ( 20 mg/day ) or placebo for 5 yrs .
24367492
Fluorescent in-situ hybridization was performed on a tissue microarray of 495 Cancerbreast tumors ( 74 % of patients ) to measure CCND1 and RSF1 copy number .
24367492
CCND1 gene amplification was observed in 8.7 % and RSF1 in 6.8 % of these patients , preferentially in Cancerestrogen receptor positive breast cancers .
24367492
Unlike CCND1 amplification , RSF1 amplification may predict for outcome in Cancerhigh-risk premenopausal breast cancer patients treated with adjuvant tamoxifen .
24373973
CancerMalignant peripheral nerve sheath tumors ( MPNSTs ) are highly aggressive sarcomas that develop sporadically or in neurofibromatosis type 1 ( NF1 ) patients .
24373973
Malignant peripheral nerve sheath tumors ( MPNSTs ) are highly Canceraggressive sarcomas that develop sporadically or in neurofibromatosis type 1 ( NF1 ) patients .
24373973
To gain insights into MPNST pathogenesis , we utilized an MPNST mouse model that allowed us to study the evolution of these Cancertumors at the transcriptome level .
24373973
Our findings reveal roles for BET bromodomains in MPNST development and report a mechanism by which bromodomain inhibition induces apoptosis through induction of proapoptotic Bim , which may representa paradigm shift in therapy for MPNST patients.Moreover , these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibitioncan shift this balance in favor of Cancercancer cell apoptosis .
24387334
Phosphatase and tensin homologue deleted on chromosome 10 ( PTEN ) is one of the most frequently disrupted tumor suppressors in Cancercancer .
24387334
The lipid phosphatase activity of PTEN antagonizes the phosphatidylinositol 3-kinase ( PI3K )/AKT/mTOR pathway to repress Cancertumor cell growth and survival .
24387334
Given the high frequency of PTEN deficiency across Cancercancer subtypes , therapeutic approaches that exploit PTEN loss-of-function could provide effective treatment strategies .
24387334
Herein , we discuss therapeutic strategies aimed at Cancercancers with loss of PTEN function , and the challenges involved in treating patients afflicted with such cancers .
24387334
Herein , we discuss therapeutic strategies aimed at cancers with loss of PTEN function , and the challenges involved in treating patients afflicted with Cancersuch cancers .
24387334
We review preclinical and clinical findings , and highlight novel strategies under development to target CancerPTENdeficient cancers .
24388723
BACKGROUND : BRAF mutations are frequent in Cancermelanoma but their prognostic significance remains unclear .
24388723
OBJECTIVE : We sought to further evaluate the prognostic value of BRAF mutations in Cancerlocalized cutaneous melanoma .
24388723
METHODS : We undertook an observational retrospective study of 147 patients with localized invasive ( stages I and II ) Cancercutaneous melanomas to determine the prognostic value of BRAF mutation status .
24388723
RESULTS : After a median follow-up of 48 months , patients with Cancerlocalized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype ( hazard ratio 2.2 , 95 % confidence interval 1.1-4 .3 ) even after adjustment for Breslow thickness , tumor ulceration , location , age , sex , and tumor mitotic rate .
24388723
RESULTS : After a median follow-up of 48 months , patients with localized melanomas with CancerBRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype ( hazard ratio 2.2 , 95 % confidence interval 1.1-4 .3 ) even after adjustment for Breslow thickness , tumor ulceration , location , age , sex , and tumor mitotic rate .
24388723
RESULTS : After a median follow-up of 48 months , patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype ( hazard ratio 2.2 , 95 % confidence interval 1.1-4 .3 ) even after adjustment for Breslow thickness , Cancertumor ulceration , location , age , sex , and tumor mitotic rate .
24388723
RESULTS : After a median follow-up of 48 months , patients with localized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype ( hazard ratio 2.2 , 95 % confidence interval 1.1-4 .3 ) even after adjustment for Breslow thickness , tumor ulceration , location , age , sex , and Cancertumor mitotic rate .
24388723
CONCLUSIONS : Our findings suggest that reappraisal of clinical treatment approaches for patients with Cancerlocalized melanoma harboring tumors with BRAF mutation might be warranted .
24388723
CONCLUSIONS : Our findings suggest that reappraisal of clinical treatment approaches for patients with localized melanoma harboring Cancertumors with BRAF mutation might be warranted .
24396464
The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in Cancerpapillary thyroid carcinoma ( PTC ) and to determine the correlation between this mutation and indicators of poor prognosis and outcome in patients with PTC .
24396464
The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma ( PTC ) and to determine the correlation between this mutation and indicators of AdverseOutcomepoor prognosis and outcome in patients with PTC .
24396464
The BRAF V600E mutation status was analyzed in 187 Cancertumor samples using the multiplex allele specific PCR method .
24396464
The BRAF V600E mutation was observed in 63.6 % ( 119/187 ) of Cancertumor tissues , predominantly in PTC specimens , and no BRAF mutation was identified in other benign-type thyroid diseases .
24396464
The BRAF V600E mutation was observed in 63.6 % ( 119/187 ) of tumor tissues , predominantly in PTC specimens , and no BRAF mutation was identified in Diseaseother benign-type thyroid diseases .
24396464
The univariate analysis indicated that the BRAF V600E mutation was associated with age , Cancertumor stage and prognosis ( P < 0.05 ) .
24396464
In addition , the frequency of the BRAF V600E mutation was significantly different in the central ( 75.3 % ) and lateral neck ( 49.3 % ) lymph nodes of patients with Cancerlymph node metastasis .
24396464
Multivariate logistic regression analysis showed that the BRAF V600E mutation ( HR , 2.471 ; 95 % CI , 1.149-5 .312 ) and Cancerlymph node metastasis ( HR , 3.003 ; 95 % CI , 1.027-8 .771 ) are independent factors that predict tumor prognosis .
24396464
Multivariate logistic regression analysis showed that the BRAF V600E mutation ( HR , 2.471 ; 95 % CI , 1.149-5 .312 ) and lymph node metastasis ( HR , 3.003 ; 95 % CI , 1.027-8 .771 ) are independent factors that predict Cancertumor prognosis .
24396464
Thus , the BRAF V600E mutation is an AdverseOutcomeindependent risk factor that may be used to predict thyroid cancer persistence and recurrence .
24396464
Thus , the BRAF V600E mutation is an independent risk factor that may be used to predict Cancerthyroid cancer persistence and recurrence .
24407160
In Cancerchronic eosinophilic leukemia , the transforming oncoprotein FIP1L1-PDGFRA is a major target of therapy .
24407160
In summary , novel PDGFR targeting TKIs may be alternative agents for the treatment of patients with Cancerimatinib resistant chronic eosinophilic leukemia .
24422672
Herein , we report a case of a difficult to characterize Cancersarcoma like lesion for which genomic profiling with clinical next generation sequencing ( NGS ) identified the molecular underpinnings of arrested progression ( stable disease ) under combination targeted therapy within a phase I clinical trial .
24422672
Herein , we report a case of a difficult to characterize sarcoma like lesion for which genomic profiling with clinical next generation sequencing ( NGS ) identified the molecular underpinnings of arrested progression ( Diseasestable disease ) under combination targeted therapy within a phase I clinical trial .
24422672
RESULTS : The histology of the Cancertumor was that of a spindle cell neoplasm , grade 2 by FNCLCC standards .
24422672
The patient had a 25 % reduction in Cancertumor ( RECIST v1 .1 ) following combination therapy consisting of sorafenib , temsirolimus , and bevazicumab within a phase I clinical trial .
24422672
This is the first report of a Cancertumor driven by a KIAA1549-BRAF fusion responding to sorafenib based combination therapy .
24439929
BACKGROUND : Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with CancerEGFR mutation positive advanced non-small-cell lung cancer ( NSCLC ) .
24439929
After central testing for EGFR mutations , treatment-naive patients ( stage IIIB or IV Cancercancer [ American Joint Committee on Cancer version 6 ] , performance status 0-1 ) were randomly assigned ( 2:1 ) to receive either oral afatinib ( 40 mg per day ) or intravenous gemcitabine 1000 mg/m ( 2 ) on day 1 and day 8 plus cisplatin 75 mg/m ( 2 ) on day 1 of a 3-week schedule for up to six cycles .
24439929
Treatment continued until Diseasedisease progression , intolerable toxic effects , or withdrawal of consent .
24439929
The most common treatment related grade 3 or 4 adverse events in the afatinib group were rash or acne ( 35 [ 14.6 % ] of 239 patients ) , diarrhoea ( 13 [ 5.4 % ] ) , and Diseasestomatitis or mucositis ( 13 [ 5.4 % ] ) , compared with neutropenia ( 30 [ 26.5 % ] of 113 patients ) , vomiting ( 22 [ 19.5 % ] ) , and leucopenia ( 17 [ 15.0 % ] ) in the gemcitabine and cisplatin group .
24439929
The most common treatment related grade 3 or 4 adverse events in the afatinib group were rash or acne ( 35 [ 14.6 % ] of 239 patients ) , diarrhoea ( 13 [ 5.4 % ] ) , and stomatitis or Diseasemucositis ( 13 [ 5.4 % ] ) , compared with neutropenia ( 30 [ 26.5 % ] of 113 patients ) , vomiting ( 22 [ 19.5 % ] ) , and leucopenia ( 17 [ 15.0 % ] ) in the gemcitabine and cisplatin group .
24439929
The most common treatment related grade 3 or 4 adverse events in the afatinib group were rash or acne ( 35 [ 14.6 % ] of 239 patients ) , diarrhoea ( 13 [ 5.4 % ] ) , and stomatitis or mucositis ( 13 [ 5.4 % ] ) , compared with Diseaseneutropenia ( 30 [ 26.5 % ] of 113 patients ) , vomiting ( 22 [ 19.5 % ] ) , and leucopenia ( 17 [ 15.0 % ] ) in the gemcitabine and cisplatin group .
24439929
The most common treatment related grade 3 or 4 adverse events in the afatinib group were rash or acne ( 35 [ 14.6 % ] of 239 patients ) , diarrhoea ( 13 [ 5.4 % ] ) , and stomatitis or mucositis ( 13 [ 5.4 % ] ) , compared with neutropenia ( 30 [ 26.5 % ] of 113 patients ) , vomiting ( 22 [ 19.5 % ] ) , and Diseaseleucopenia ( 17 [ 15.0 % ] ) in the gemcitabine and cisplatin group .
24457318
Predictors of EGFR-TKI responsiveness in CancerEGFR-mutant non small cell lung cancer ( NSCLC ) patients , however , have not been well investigated .
24457318
RESULTS : The objective response rate was 50.0 % ( 95 % confidence interval , CI , 38.6-61 .4 % ) and the Diseasedisease control rate was 91.4 % ( 95 % CI , 82.5-96 .0 % ) .
24457318
In multivariate analysis , Canceradenocarcinoma ( hazard ratio , HR , 12.25 ; 95 % CI , 37.7-41 .10 ; p < 0.001 ) and major mutations ( deletions in exon 19 and L858R point mutation in exon 21 ; HR , 2.46 ; 95 % CI , 1.14-5 .28 ; p = 0.022 ) were significant predictors of longer PFS .
24457318
CONCLUSION : Major mutations and Canceradenocarcinoma histology were independent predictors of better treatment outcome in EGFR-mutant NSCLC patients who received EGFR-TKIs .
24469055
CancerLung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK and RAS pathway members KRAS , EGFR , BRAF and ERBB2 , and translocations involving ALK , RET and ROS1 .
24469055
Identification of these oncogenic events has transformed the treatment of Cancerlung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations .
24469055
However , such mutations have been reported in only ~ 55 % of Cancerlung adenocarcinoma cases in the United States , suggesting other mechanisms of malignancy are involved in the remaining cases .
24469055
However , such mutations have been reported in only ~ 55 % of lung adenocarcinoma cases in the United States , suggesting other mechanisms of Cancermalignancy are involved in the remaining cases .
24469055
Here we report somatic mutations in the small GTPase gene RIT1 in ~ 2 % of Cancerlung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein .
24469055
RIT1 switch II domain mutations are mutually exclusive with all Cancerother known lung adenocarcinoma driver mutations .
24469055
These data identify RIT1 as a driver oncogene in a specific subset of Cancerlung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1 mutated tumors .
24469055
These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1 mutated Cancertumors .
24478318
BACKGROUND : Crizotinib is approved to treat Canceradvanced ALK positive non-small-cell lung cancer ( NSCLC ) , but most patients ultimately develop progressive disease ( PD ) .
24478318
BACKGROUND : Crizotinib is approved to treat advanced ALK positive non-small-cell lung cancer ( NSCLC ) , but most patients ultimately develop Diseaseprogressive disease ( PD ) .
24495407
We have investigated the potential for the Cancerp16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma .
24495407
We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in Cancermelanoma .
24495407
In a cohort of 143 patients with Cancerprimary invasive melanoma , we used fluorescence in situ hybridization to detect gene copy number variations ( CNVs ) in CDK4 , CCND1 , and CDKN2A and immunohistochemistry to determine protein expression .
24495407
CNVs were common in Cancermelanoma , with gain of CDK4 or CCND1 in 37 and 18 % of cases , respectively , and hemizygous or homozygous loss of CDKN2A in 56 % .
24495407
The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with Cancerpoorer melanoma specific survival .
24495407
In 47 Cancermelanoma cell lines homozygous loss , methylation or mutation of CDKN2A gene or loss of protein ( p16 ( INK ) ( 4A ) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991 , while RB1 loss predicted resistance .
24496303
Multivariable analysis distinguished CALR (-) ASXL1 ( + ) mutational status as the most AdverseOutcomesignificant risk factor for survival : HR 3.7 vs 2.8 for age > 65 years vs 2.7 for unfavorable karyotype .
24504448
BACKGROUND : BRAF is mutated in ~ 42 % of Cancerhuman melanomas ( COSMIC .
24504448
http://www.sanger.ac.uk/genetics/CGP/cosmic/ ) and pharmacological BRAF inhibitors such as vemurafenib and dabrafenib achieve dramatic responses in patients whose Cancertumours harbour BRAF ( V600 ) mutations .
24504448
Objective responses occur in ~ 50 % of patients and Diseasedisease stabilisation in a further ~ 30 % , but ~ 20 % of patients present primary or innate resistance and do not respond .
24504448
Here , we investigated the underlying cause of treatment failure in a patient with CancerBRAF mutant melanoma who presented primary resistance .
24504448
METHODS : We carried out whole-genome sequencing and single nucleotide polymorphism ( SNP ) array analysis of five Cancermetastatic tumours from the patient .
24504448
We validated mechanisms of resistance in a cell line derived from the patient 's Cancertumour .
24504448
RESULTS : We observed that the majority of the single-nucleotide variants identified were shared across all Cancertumour sites , but also saw site specific copy-number alterations in discrete cell populations at different sites .
24504448
We found that two ubiquitous mutations mediated resistance to BRAF inhibition in these Cancertumours .
24504448
CONCLUSIONS : Our analyses show that the five metastases arose from a common progenitor and acquired additional alterations after Diseasedisease dissemination .
24504448
These mutations were present in all five Cancertumours and in a tumour sample taken before BRAF inhibitor treatment was administered .
24504448
These mutations were present in all five tumours and in a Cancertumour sample taken before BRAF inhibitor treatment was administered .
24504448
Inhibition of both pathways was required to block Cancertumour cell growth , suggesting that combined targeting of these pathways could have been a valid therapeutic approach for this patient .
24508103
BACKGROUND : In the BRIM-3 trial , vemurafenib was associated with AdverseOutcomerisk reduction versus dacarbazine of both death and progression in patients with advanced BRAF ( V600 ) mutation positive melanoma .
24508103
BACKGROUND : In the BRIM-3 trial , vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF ( V600 ) Cancermutation positive melanoma .
24508103
METHODS : Patients older than 18 years , with Cancertreatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF ( V600 ) mutations were eligible .
24508103
METHODS : Patients older than 18 years , with treatment-naive metastatic melanoma and whose Cancertumour tissue was positive for BRAF ( V600 ) mutations were eligible .
24508103
For the 598 ( 91 % ) patients with BRAF ( V600E ) Diseasedisease , median overall survival in the vemurafenib group was 13.3 months ( 95 % CI 11.9-14 .9 ) compared with 10.0 months ( 8.0-14 .0 ) in the dacarbazine group ( HR 0.75 [ 95 % CI 0.60-0 .93 ] ; p = 0.0085 ) ; median progression-free survival was 6.9 months ( 95 % CI 6.2-7 .0 ) and 1.6 months ( 1.6-2 .1 ) , respectively ( HR 0.39 [ 95 % CI 0.33-0 .47 ] ; p < 0.0001 ) .
24508103
For the 57 ( 9 % ) patients with BRAF ( V600K ) Diseasedisease , median overall survival in the vemurafenib group was 14.5 months ( 95 % CI 11.2-not estimable ) compared with 7.6 months ( 6.1-16 .6 ) in the dacarbazine group ( HR 0.43 [ 95 % CI 0.21-0 .90 ] ; p = 0.024 ) ; median progression-free survival was 5.9 months ( 95 % CI 4.4-9 .0 ) and 1.7 months ( 1.4-2 .9 ) , respectively ( HR 0.30 [ 95 % CI 0.16-0 .56 ] ; p < 0.0001 ) .
24508103
The most frequent grade 3-4 events were Cancercutaneous squamous-cell carcinoma ( 65 [ 19 % ] of 337 patients ) and keratoacanthomas ( 34 [ 10 % ] ) , rash ( 30 [ 9 % ] ) , and abnormal liver function tests ( 38 [ 11 % ] ) in the vemurafenib group and neutropenia ( 26 [ 9 % ] of 287 patients ) in the dacarbazine group .
24508103
The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma ( 65 [ 19 % ] of 337 patients ) and Cancerkeratoacanthomas ( 34 [ 10 % ] ) , rash ( 30 [ 9 % ] ) , and abnormal liver function tests ( 38 [ 11 % ] ) in the vemurafenib group and neutropenia ( 26 [ 9 % ] of 287 patients ) in the dacarbazine group .
24508103
The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma ( 65 [ 19 % ] of 337 patients ) and keratoacanthomas ( 34 [ 10 % ] ) , rash ( 30 [ 9 % ] ) , and abnormal liver function tests ( 38 [ 11 % ] ) in the vemurafenib group and Diseaseneutropenia ( 26 [ 9 % ] of 287 patients ) in the dacarbazine group .
24512910
BACKGROUND & AIMS : Patients with Cancercolorectal tumors with microsatellite instability ( MSI ) have better prognoses than patients with tumors without MSI , but have a poor response to 5-fluorouracil-based chemotherapy .
24512910
BACKGROUND & AIMS : Patients with colorectal tumors with microsatellite instability ( MSI ) have better prognoses than patients with Cancertumors without MSI , but have a poor response to 5-fluorouracil-based chemotherapy .
24512910
A dominant negative form of heat shock protein ( HSP ) 110 ( HSP110DE9 ) expressed by Cancercancer cells with MSI , via exon skipping caused by somatic deletions in the T ( 17 ) intron repeat , sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T ( 17 ) could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin .
24512910
A dominant negative form of heat shock protein ( HSP ) 110 ( HSP110DE9 ) expressed by cancer cells with MSI , via exon skipping caused by somatic deletions in the T ( 17 ) intron repeat , sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T ( 17 ) could be used to identify patients with Cancercolorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin .
24512910
By using polymerase chain reaction and fragment analysis , we examined how the size of somatic allelic deletions in HSP110 T ( 17 ) affected the HSP110 protein expressed by Cancertumor cells .
24512910
We screened 329 consecutive patients with stage II-III Cancercolorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T ( 17 ) .
24512910
CancerTumor cells with large deletions in T ( 17 ) had increased ratios of HSP110DE9 : HSP110 , owing to the loss of expression of full-length HSP110 .
24512910
Deletions in HSP110 T ( 17 ) were mostly biallelic in Cancerprimary tumor samples with MSI .
24512910
Patients with Cancerstage II-III cancer who received chemotherapy and had large HSP110 T ( 17 ) deletions ( > = 5 bp ; 18 of 77 patients , 23.4 % ) had longer times of relapse-free survival than patients with small or no deletions ( < = 4 bp ; 59 of 77 patients , 76.6 % ) in multivariate analysis ( hazard ratio , 0.16 ; 95 % confidence interval , 0.012-0 .8 ; P = .03 ) .
24512910
CONCLUSIONS : About 25 % of patients with Cancerstages II-III colorectal tumors with MSI have an excellent response to chemotherapy , due to large , biallelic deletions in the T ( 17 ) intron repeat of HSP110 in tumor DNA .
24512910
CONCLUSIONS : About 25 % of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy , due to large , biallelic deletions in the T ( 17 ) intron repeat of HSP110 in Cancertumor DNA .
24512939
Several molecular markers have been described that help to classify patients with Canceracute myeloid leukemia ( AML ) , a heterogeneous hematopoietic tissue neoplasm , into risk groups .
24512939
Several molecular markers have been described that help to classify patients with acute myeloid leukemia ( AML ) , a heterogeneous hematopoietic tissue neoplasm , into AdverseOutcomerisk groups .
24512939
We determined the frequency of DNMT3A mutations , their associations with clinical and molecular characteristics and outcome , in primary , cytogenetically-normal AML ( CN-AML ) and DiseaseCN-myelodysplastic syndrome ( MDS ) .
24512939
DNMT3A mutated patients had Diseaseshorter overall disease survival ( p < 0.001 ) and disease-free survival ( p = 0.014 ) when the entire patient cohort was considered , which remained significant in multivariate analysis .
24512939
We conclude that DNMT3A R882 mutations are recurrent molecular aberrations in CN-AML , less frequent in CN-MDS , and that testing for R882 mutations may provide a useful tool for refining AdverseOutcomerisk classification of CN-AML .
24550739
CancerAdvanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited .
24550739
During the course of a clinical trial of whole genomic sequencing seeking druggable targets , we examined six patients with Canceradvanced cholangiocarcinoma .
24550739
Integrated genome-wide and whole transcriptome sequence analyses were performed on Cancertumors from six patients with advanced , sporadic intrahepatic cholangiocarcinoma ( SIC ) to identify potential therapeutically actionable events .
24550739
Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced , Cancersporadic intrahepatic cholangiocarcinoma ( SIC ) to identify potential therapeutically actionable events .
24550739
After progression on pazopanib , the same patient also had Diseasestable disease on ponatinib , a pan-FGFR inhibitor ( in vitro , FGFR2 IC50 = ~ 8 nM ) .
24550739
Rapid and Diseaserobust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib , an EGFR kinase inhibitor .
24550739
Rapid and robust disease regression was noted in this ERRFI1 inactivated Cancertumor when treated with erlotinib , an EGFR kinase inhibitor .
24550739
FGFR2 fusions and ERRFI mutations may represent novel targets in Cancersporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations .
24559322
Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of Cancertumor angiogenesis ( VEGFR1 , 2 , 3 ; angiopoietin-1 receptor ) , oncogenesis ( stem cell growth factor receptor ; RET ; BRAF including BRAFV600E ) , and tumor microenvironment ( PDGFR-beta and FGFR ) .
24559322
Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of tumor angiogenesis ( VEGFR1 , 2 , 3 ; angiopoietin-1 receptor ) , oncogenesis ( stem cell growth factor receptor ; RET ; BRAF including BRAFV600E ) , and Cancertumor microenvironment ( PDGFR-beta and FGFR ) .
24559322
Based on data from the Phase III CORRECT study , regorafenib stands as a further option for patient affected by Cancermetastatic colorectal cancer who have exhausted previous available therapies .
24559322
Its multi targeted effect might explain activity in advanced lines of treatment , when Cancercancer cells have been heavily challenged with previous lines of therapy and potentially developed multiple mechanisms of resistance , but also makes difficult to identify predictive biomarkers .
24559322
In this article we examine preclinical as well as clinical data of regorafenib in the therapy of Cancermetastatic colorectal cancer , challenges for potential markers of efficacy and its role in the treatment algorithm .
24569458
Targeted Cancercancer therapies often induce " outlier " responses in molecularly defined patient subsets .
24569458
One patient with Canceradvanced-stage lung adenocarcinoma , who was treated with oral sorafenib , demonstrated a near-complete clinical and radiographic remission for 5 years .
24569458
Whole-genome sequencing and RNA sequencing of Cancerprimary tumor and normal samples from this patient identified a somatic mutation , ARAF S214C , present in the cancer genome and expressed at high levels .
24569458
Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation , ARAF S214C , present in the Cancercancer genome and expressed at high levels .
24569458
Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1 % of an independent cohort of Cancerlung adenocarcinoma cases .
24569458
These results suggest that mutant ARAF is an oncogenic driver in Cancerlung adenocarcinoma and an indicator of sorafenib response .
24570209
BRAF ( V600E ) is the most frequent genetic mutation in Cancerpapillary thyroid cancer ( PTC ) and has been reported as an independent predictor of poor prognosis of these patients .
24570209
BRAF ( V600E ) is the most frequent genetic mutation in papillary thyroid cancer ( PTC ) and has been reported as an independent predictor of AdverseOutcomepoor prognosis of these patients .
24570209
Recently , immunohistochemistry using VE1 , a mouse anti-human BRAF ( V600E ) antibody , has been reported as a highly reliable technique in detecting BRAF mutated thyroid and Cancernonthyroid cancers .
24570209
After surgery , final histology demonstrated 21 Cancercancers and 9 benign lesions .
24570209
One Cancerfollicular thyroid cancer and 4 benign lesions were assessed at CNB as uncertain follicular neoplasm .
24571676
BACKGROUND : Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in Diseaseleukaemia pathogenesis , including RAS mutation ( RASmut ) in acute myeloid leukaemia ( AML ) , which has been associated with intra-uterine chemical exposures .
24571676
BACKGROUND : Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis , including RAS mutation ( RASmut ) in Diseaseacute myeloid leukaemia ( AML ) , which has been associated with intra-uterine chemical exposures .
24571676
A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with Diseaseearly age leukaemia ( EAL ) .
24571676
Samples from 150 Diseaseacute lymphoblastic leukaemia ( ALL ) and 85 AML were included .
24571676
A considerable increased AdverseOutcomerisk for EAL with the combination of RASmut and NQO1 609CT ( OR , 4.24 , 95 % CI , 1.24-14 .50 ) was observed .
24571676
CONCLUSIONS : Our data demonstrated the AdverseOutcomeincreased risk association between maternal smoking and EAL with MLL-r .
24571676
Additionally , suggests that children second-hand tobacco exposures are associated with increased AdverseOutcomerisk of EAL with RASmut modulated by NQO1 rs1800566 ( C609T ) .
24576830
CancerMelanoma is a disease characterized by lesions that activate ERK .
24576830
Melanoma is a Diseasedisease characterized by lesions that activate ERK .
24576830
Although 70 % of Cancercutaneous melanomas harbor activating mutations in the BRAF and NRAS genes , the alterations that drive tumor progression in the remaining 30 % are largely undefined .
24576830
Although 70 % of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes , the alterations that drive Cancertumor progression in the remaining 30 % are largely undefined .
24576830
Vemurafenib , a selective inhibitor of RAF kinases , has clinical utility restricted to CancerBRAF-mutant tumors .
24576830
MEK inhibitors , which have shown clinical activity in CancerNRAS-mutant melanoma , may be effective in other ERK pathway dependent settings .
24576830
Here , we investigated a panel of Cancermelanoma cell lines wild type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment .
24576830
Notably , alterations in NF1 frequently co-occurred with RAS and BRAF alterations in Cancermelanoma .
24576830
We conclude that loss of NF1 is common in Cancercutaneous melanoma and is associated with RAS activation , MEK-dependence , and resistance to RAF inhibition .
24577089
DiseaseInfection with human papillomaviruses ( HPVs ) characterizes a distinct subset of head and neck squamous cell cancers ( HNSCCs ) .
24577089
Infection with human papillomaviruses ( HPVs ) characterizes a distinct subset of head and Cancerneck squamous cell cancers ( HNSCCs ) .
24577089
In addition , we have stably expressed the HPV oncogenes E6 and E7 in Cancercetuximab sensitive cancer cell lines to specifically investigate their role in the antibody response .
24577089
Cetuximab effectively inhibited the growth of E6- and CancerE7 expressing tumors grafted in NOD and SCID mice .
24577089
In support , formalin fixed , Cancerparaffin embedded tumor samples from cetuximab treated patients with recurrent or metastatic HNSCC were probed for p16 ( INK4a ) expression , an established biomarker of HPV infection .
24577089
In support , formalin fixed , paraffin embedded tumor samples from cetuximab treated patients with recurrent or metastatic HNSCC were probed for p16 ( INK4a ) expression , an established biomarker of DiseaseHPV infection .
24577089
Response rates ( 45.5 % versus 45.5 % ) and median progression-free survival ( 97 versus 92 days ) following cetuximab based therapy were similar in patients with p16 ( INK4A )-positive and p16 ( CancerINK4A )-negative tumors .
24577117
BACKGROUND : CancerTumor human papillomavirus ( HPV ) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) .
24577117
BACKGROUND : Tumor human papillomavirus ( HPV ) status is an important prognostic factor in locoregionally Canceradvanced squamous cell carcinoma of the head and neck ( SCCHN ) .
24577117
Prognostic value in recurrent and/or metastatic ( R/M ) Diseasedisease remains to be confirmed .
24577117
This retrospective analysis of the EXTREME trial , comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN , investigated efficacy and prognosis according to Cancertumor p16 and HPV status .
24577117
RESULTS : Altogether , 416 of 442 patients had Cancertumor samples available for p16 and HPV : 10 % of tumors were p16 positive and 5 % were HPV positive .
24577117
RESULTS : Altogether , 416 of 442 patients had tumor samples available for p16 and HPV : 10 % of Cancertumors were p16 positive and 5 % were HPV positive .
24577117
Adding cetuximab to chemotherapy improved survival , irrespective of Cancertumor p16 or HPV status .
24577117
Subgroup analysis of patients with Canceroropharyngeal cancer demonstrated a similar pattern to all evaluable patients .
24577117
CONCLUSION : The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of Cancertumor p16 and HPV status .
24578576
CancerFibrolamellar hepatocellular carcinoma ( FL-HCC ) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis .
24578576
Fibrolamellar hepatocellular carcinoma ( FL-HCC ) is a Cancerrare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis .
24578576
Fibrolamellar hepatocellular carcinoma ( FL-HCC ) is a rare liver tumor affecting adolescents and young adults with no history of Diseaseprimary liver disease or cirrhosis .
24578576
The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1 , a homolog of the molecular chaperone DNAJ , fused in frame with PRKACA , the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in Cancertumor tissue , and a cell culture assay indicated that it retains kinase activity .
24578576
Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100 % of the FL-HCCs examined ( 15/15 ) suggests that this genetic alteration contributes to Cancertumor pathogenesis .
24583796
Dabrafenib and trametinib were approved for use as monotherapies in CancerBRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration ( FDA ) in 2013 , and most recently , their use in combination has received accelerated FDA approval .
24583796
The phase III study of dabrafenib in BRAF ( V600E ) Cancermetastatic melanoma reported rapid tumor regression in most patients and a 59 % objective RECIST response rate .
24583796
The phase III study of dabrafenib in BRAF ( V600E ) metastatic melanoma reported Cancerrapid tumor regression in most patients and a 59 % objective RECIST response rate .
24583796
DiseaseToxicities were well tolerated and different from those reported for vemurafenib , the first FDA approved BRAF inhibitor .
24583796
A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy , with Diseaseless cutaneous toxicity .
24583796
Here , we review the clinical development of both drugs as monotherapies and in combination , and discuss their role in the management of CancerBRAF-mutant melanoma .
24586605
BACKGROUND : The impact of CancerBRAF tumor mutations on the natural course of disease of melanoma patients is controversial .
24586605
BACKGROUND : The impact of BRAF tumor mutations on the natural course of Diseasedisease of melanoma patients is controversial .
24586605
BACKGROUND : The impact of BRAF tumor mutations on the natural course of disease of Cancermelanoma patients is controversial .
24586605
CONCLUSIONS : No differences in prognosis were observed according to the BRAF mutational status in patients with Cancerdistant metastasis treated with monochemotherapy .
24586741
Clinicopathologic characteristics of Cancercancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown .
24586741
METHODS : Using multiplex gene panels we evaluated how the FBXW7 mutation affected the Cancercancer phenotype of patients referred to a phase I clinic starting January 2012 .
24586741
Among Cancertumor types with more than 10 patients tested , FBXW7 mutations occurred in colorectal cancer ( 7/49 ; 14.3 % ) , squamous cell cancer of head and neck ( 2/18 ; 11.1 % ) , liver ( 1/13 ; 7.7 % ) , and ovarian cancers ( 1/40 ; 2.5 % ) .
24586741
Among tumor types with more than 10 patients tested , FBXW7 mutations occurred in Cancercolorectal cancer ( 7/49 ; 14.3 % ) , squamous cell cancer of head and neck ( 2/18 ; 11.1 % ) , liver ( 1/13 ; 7.7 % ) , and ovarian cancers ( 1/40 ; 2.5 % ) .
24586741
Among tumor types with more than 10 patients tested , FBXW7 mutations occurred in colorectal cancer ( 7/49 ; 14.3 % ) , Cancersquamous cell cancer of head and neck ( 2/18 ; 11.1 % ) , liver ( 1/13 ; 7.7 % ) , and ovarian cancers ( 1/40 ; 2.5 % ) .
24586741
Among tumor types with more than 10 patients tested , FBXW7 mutations occurred in colorectal cancer ( 7/49 ; 14.3 % ) , squamous cell cancer of head and neck ( 2/18 ; 11.1 % ) , liver ( 1/13 ; 7.7 % ) , and Cancerovarian cancers ( 1/40 ; 2.5 % ) .
24586741
The mutation occurred in isolation in only 2/17 ( 12 % ) patients , and KRAS was frequently found as a concomitant mutation , especially in patients with Cancercolorectal cancer ( 6/7 ; 86 % ) .
24586741
One patient with Cancerliver cancer ( fibrolamellar subtype ) continues to have a prolonged stable disease for 6.8+ months .
24586741
One patient with liver cancer ( fibrolamellar subtype ) continues to have a Diseaseprolonged stable disease for 6.8+ months .
24586741
CONCLUSION : In patients with Canceradvanced cancers , somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations , which can contribute to limited therapeutic efficacy of mTOR inhibitors .
24587245
Stathmin is a prognostic marker in Cancermany cancers , including endometrial cancer .
24587245
Stathmin is a prognostic marker in many cancers , including Cancerendometrial cancer .
24587245
Preclinical studies , predominantly in Cancerbreast cancer , have suggested that stathmin may additionally be a predictive marker for response to paclitaxel .
24587245
We first evaluated the response to paclitaxel in Cancerendometrial cancer cell lines before and after stathmin knock-down .
24587245
Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in Cancermetastatic endometrial cancer in relation to stathmin protein level in tumors .
24587245
Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in metastatic endometrial cancer in relation to stathmin protein level in Cancertumors .
24587245
Stathmin level was also determined in metastatic lesions , analyzing changes in biomarker status on Diseasedisease progression .
24587245
Knock-down of stathmin improved sensitivity to paclitaxel in Cancerendometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel .
24587245
In clinical samples , high stathmin level was demonstrated to be associated with poor response to paclitaxel containing chemotherapy and to reduced Diseasedisease specific survival only in patients treated with such combination .
24587245
This study suggests , supported by both preclinical and clinical data , that stathmin could be a predictive biomarker for response to paclitaxel treatment in Cancerendometrial cancer .
24588908
BACKGROUND : Gain of function mutations in B-RAF and N-RAS occur frequently in Cancermelanoma , leading to mitogen activating protein kinase ( MAPK ) pathway activation , and this pathway is the target of drugs in development .
24588908
Our purpose was to study clinical characteristics of patients with mutations in this pathway and to determine activity of inhibitors of B-RAF and MEK in short term cultures grown from Cancertumors of some of these patients .
24588908
METHODS : Clinical and pathologic data were collected retrospectively on Cancermelanoma patients tested for B-RAF and N-RAS mutations at the Yale Cancer Center and associations with survival were determined .
24588908
We studied in vitro activity of the pan-RAF inhibitor , RAF265 , and the MEK inhibitor , MEK162 , in 22 Cancermelanoma short term cultures .
24588908
We further characterized the effect of MEK inhibition on apoptosis and growth of Cancermelanoma cultures .
24588908
RESULTS : In a cohort of 144 Cancermetastatic melanoma patients we found that patients with N-RAS mutant melanoma had a worse prognosis .
24588908
RESULTS : In a cohort of 144 metastatic melanoma patients we found that patients with CancerN-RAS mutant melanoma had a worse prognosis .
24588908
These patients were more likely to have brain metastases at the time of presentation with Diseasemetastatic disease than their N-RAS-wild-type counterparts .
24588908
All CancerN-RAS mutant melanoma cultures tested in our study ( n = 7 ) were sensitive to MEK inhibition 162 .
24588908
Clonogenic survival was significantly reduced in Cancersensitive melanoma cell cultures .
24588908
CONCLUSIONS : The prognosis of patients with Cancermelanoma expressing constitutively active N-RAS is poor , consistent with studies performed at other institutions .
24588908
CancerN-RAS mutant melanoma cultures appear to be particularly sensitive to MEK162 , supporting ongoing clinical trials with MEK162 in N-RAS mutated melanoma .
24588908
N-RAS mutant melanoma cultures appear to be particularly sensitive to MEK162 , supporting ongoing clinical trials with MEK162 in N-RAS mutated Cancermelanoma .
24594804
BACKGROUND : CancerColorectal cancer ( CRC ) is a heterogeneous disease with multiple underlying causative genetic mutations .
24594804
BACKGROUND : Colorectal cancer ( CRC ) is a Diseaseheterogeneous disease with multiple underlying causative genetic mutations .
24594804
The presence of BRAFV600E mutation can determine the response of a Cancertumor to chemotherapy .
24595080
The purpose of the study was to evaluate whether the tailored chemotherapy based on RRM1 immunohistochemical ( IHC ) expression had any benefit for patients with Canceradvanced non small cell lung cancer ( NSCLC ) .
24595080
RESULTS : There were statistically significant improvements between the personalized therapy group versus the standard therapy group in Diseasedisease control rate ( 82.9 % vs 55.3 % , P = 0.004 ) , and PFS ( median : 5.5 months vs 3.0 months , P = 0.005 ) .
24608574
Somatic PIK3CA mutations are frequently found in Cancersolid tumors , raising the hypothesis that selective inhibition of PI3Kalpha may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase ( PI3K ) family .
24608574
Somatic PIK3CA mutations are frequently found in solid tumors , raising the hypothesis that selective inhibition of PI3Kalpha may have robust efficacy in CancerPIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase ( PI3K ) family .
24608574
The compound selectivity combined with excellent drug like properties translates to dose- and time dependent inhibition of PI3Kalpha signaling in vivo , resulting in robust therapeutic efficacy and tolerability in CancerPIK3CA dependent tumors .
24608574
Novel targeted therapeutics such as NVP-BYL719 , designed to modulate aberrant functions elicited by Cancercancer specific genetic alterations upon which the disease depends , require well defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients .
24608574
Novel targeted therapeutics such as NVP-BYL719 , designed to modulate aberrant functions elicited by cancer specific genetic alterations upon which the Diseasedisease depends , require well defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients .
24608574
Here , we also describe the application of the CancerCancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation , respectively .
24623981
PURPOSE : Subclones bearing the epidermal growth factor receptor ( EGFR ) T790M mutation concomitant with deletional mutation in exon 19 ( Del19 ) or a point mutation in exon 21 ( L858R ) have been reported in Cancernon small cell lung cancer patients before any EGFR tyrosine kinase inhibitor ( TKI ) treatment .
24623981
CONCLUSION : The meta-analysis reported here found that pretreatment T790M mutation had a negative impact on the PFS of Cancernon small cell lung cancer patients with a Del19 or L858R EGFR mutation who received EGFR TKI treatment .
24625776
We identified an exceptional responder in a phase I study of pazopanib and everolimus in Canceradvanced solid tumors .
24625776
The use of precision ( or " personalized " ) medicine approaches to screen patients with Cancercancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR .
24631838
Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in Cancercancer , but few mutations have been characterized in MTOR , the gene encoding the mTOR kinase .
24631838
Using publicly Canceravailable tumor genome sequencing data , we generated a comprehensive catalog of mTOR pathway mutations in cancer , identifying 33 MTOR mutations that confer pathway hyperactivation .
24631838
Using publicly available tumor genome sequencing data , we generated a comprehensive catalog of mTOR pathway mutations in Cancercancer , identifying 33 MTOR mutations that confer pathway hyperactivation .
24631838
The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in Cancermultiple cancer types , with one cluster particularly prominent in kidney cancer .
24631838
The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types , with one cluster particularly prominent in Cancerkidney cancer .
24631838
Finally , Cancercancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts , suggesting that such mutations confer mTOR pathway dependency .
24633157
Angiosarcoma is an Canceraggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema .
24633157
Previous work has identified aberrant angiogenesis , including occasional somatic mutations in angiogenesis signaling genes , as a key driver of Cancerangiosarcoma .
24633157
Here we employed whole-genome , whole-exome and targeted sequencing to study the somatic changes underpinning primary and Cancersecondary angiosarcoma .
24633157
The endothelial phosphatase PTPRB , a negative regulator of vascular growth factor tyrosine kinases , harbored predominantly truncating mutations in 10 of 39 Cancertumors ( 26 % ) .
24633157
Overall , 15 of 39 Cancertumors ( 38 % ) harbored at least one driver mutation in angiogenesis signaling genes .
24633157
Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in Cancerangiosarcoma .
24636847
Acquired resistance of epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) has been developed as an important clinical problem though EGFR-TKI such as gefitinib , erlotinib and afatinib [ 1,2 ] has achieved 8-14 months of progression free survival in Canceradvanced non small cell lung cancer ( NSCLC ) patient with EGFR mutation .
24636847
We report a case here that an Canceradvanced lung adenocarcinoma with L858R mutation responded well to pemetrexed rechallenge after acquired resistance of erlotinib .
24651015
Smoothened ( SMO ) inhibitors recently entered clinical trials for Cancersonic-hedgehog-driven medulloblastoma ( SHH-MB ) .
24651015
Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition , whereas Cancertumors harboring an SUFU mutation or MYCN amplification were primarily resistant .
24653627
OBJECTIVE : The epidermal growth factor receptor ( EGFR ) inhibitors monoclonal antibodies ( MoAbs ) have already shown the therapeutic effectiveness in patients with Cancermetastatic colorectal cancer ( mCRC ) .
24653627
CONCLUSIONS : This meta-analysis suggests that EGFR GCN represents a predictive biomarker for Cancertumor response in mCRC patients treated with MoAbs regardless of KRAS mutation .
24658004
CancerSmall cell carcinoma of the ovary , hypercalcemic type ( SCCOHT ) is a rare , highly aggressive form of ovarian cancer primarily diagnosed in young women .
24658004
Small cell carcinoma of the ovary , hypercalcemic type ( SCCOHT ) is a rare , highly aggressive form of Cancerovarian cancer primarily diagnosed in young women .
24658004
We identified inactivating biallelic SMARCA4 mutations in 100 % of the 12 CancerSCCOHT tumors examined .
24658966
Human epidermal growth factor receptor ( EGFR ) has become a well established target for the treatment of patients with Cancernon small cell lung cancer ( NSCLC ) .
24662454
INTRODUCTION : The phase III FLEX study ( NCT00148798 ) in Canceradvanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor ( EGFR ) ( immunohistochemistry score of > = 200 ; scale 0-300 ) .
24662454
INTRODUCTION : The phase III FLEX study ( NCT00148798 ) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose Cancertumors expressed high levels of epidermal growth factor receptor ( EGFR ) ( immunohistochemistry score of > = 200 ; scale 0-300 ) .
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We assessed whether the treatment effect was also modulated in FLEX study patients by Cancertumor EGFR mutation status .
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METHODS : A Cancertumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 ( 86 % ) FLEX study patients .
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Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to Cancertumor EGFR mutation status .
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RESULTS : Mutations in EGFR exons 18 to 21 were detected in 133 of 971 Cancertumors ( 14 % ) , 970 of which were also evaluable for EGFR expression level .
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In the high EGFR expression group ( immunohistochemistry score of > = 200 ) , a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type ( including T790M mutant ) Cancertumors .
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Although patient numbers were small , those in the high EGFR expression group whose Cancertumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy .
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CONCLUSIONS : The survival benefit associated with the addition of cetuximab to first-line chemotherapy for Canceradvanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status .
24666267
BACKGROUND : In Cancermetastatic colorectal cancer , mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab .
24666267
BACKGROUND : In metastatic colorectal cancer , mutation testing for KRAS exon 2 is widely implemented to select patients with Cancerwild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab .
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The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in Cancercolorectal cancer is uncertain , which led us to systematically review the impact of alterations in KRAS ( outside of exon 2 ) , NRAS , BRAF , PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment .
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CONCLUSIONS : Meta-analysis suggests that mutations in KRAS exons 3 and 4 , NRAS , BRAF and PIK3CA and non functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in Cancermetastatic colorectal cancer .
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BACKGROUND : CancerNon-small-cell lung cancer ( NSCLC ) harboring the anaplastic lymphoma kinase gene ( ALK ) rearrangement is sensitive to the ALK inhibitor crizotinib , but resistance invariably develops .
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BACKGROUND : Non-small-cell lung cancer ( NSCLC ) harboring the Canceranaplastic lymphoma kinase gene ( ALK ) rearrangement is sensitive to the ALK inhibitor crizotinib , but resistance invariably develops .
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METHODS : In this phase 1 study , we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with Canceradvanced cancers harboring genetic alterations in ALK .
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CancerTumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib .
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Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had Diseasedisease progression during treatment with crizotinib .
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The maximum tolerated dose of ceritinib was 750 mg once daily ; dose limiting toxic events included diarrhea , vomiting , dehydration , elevated aminotransferase levels , and Diseasehypophosphatemia .
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CONCLUSIONS : Ceritinib was highly active in patients with advanced , ALK rearranged NSCLC , including those who had had Diseasedisease progression during crizotinib treatment , regardless of the presence of resistance mutations in ALK .
24670642
Treatment of BRAF ( V600E ) Cancermutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective , but resistance develops invariably .
24670642
In contrast , Cancercolon cancers that harbour the same BRAF ( V600E ) mutation are intrinsically resistant to BRAF inhibitors , due to feedback activation of the epidermal growth factor receptor ( EGFR ) .
24670642
Here we show that 6 out of 16 Cancermelanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors .
24670642
Using a chromatin-regulator-focused short hairpin RNA ( shRNA ) library , we find that suppression of sex determining region Y-box 10 ( SOX10 ) in Cancermelanoma causes activation of TGF-beta signalling , thus leading to upregulation of EGFR and platelet derived growth factor receptor-beta ( PDGFRB ) , which confer resistance to BRAF and MEK inhibitors .
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Expression of EGFR in Cancermelanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene induced senescence .
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In a heterogeneous population of Cancermelanoma cells having varying levels of SOX10 suppression , cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug , but this is reversed when the drug treatment is discontinued .
24670642
We find evidence for SOX10 loss and/or activation of TGF-beta signalling in 4 of the 6 CancerEGFR positive drug resistant melanoma patient samples .
24670642
Our findings provide a rationale for why some BRAF or CancerMEK inhibitor resistant melanoma patients may regain sensitivity to these drugs after a ' drug holiday ' and identify patients with EGFR positive melanoma as a group that may benefit from re-treatment after a drug holiday .
24670642
Our findings provide a rationale for why some BRAF or MEK inhibitor resistant melanoma patients may regain sensitivity to these drugs after a ' drug holiday ' and identify patients with CancerEGFR positive melanoma as a group that may benefit from re-treatment after a drug holiday .
24675041
CancerNon small cell lung cancers ( NSCLC ) harboring anaplastic lymphoma kinase ( ALK ) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor ( TKI ) crizotinib .
24675041
Non small cell lung cancers ( NSCLC ) harboring Canceranaplastic lymphoma kinase ( ALK ) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor ( TKI ) crizotinib .
24675041
These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK positive NSCLC with Diseasecrizotinib resistant disease .
24685132
There are no effective therapies for the ~ 30 % of Cancerhuman malignancies with mutant RAS oncogenes .
24685132
Using a kinome centered synthetic lethality screen , we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and Cancercolon cancer cells to MEK inhibitors .
24685132
These data suggest a combination strategy for treating KRAS mutant colon and Cancerlung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment .
24685132
These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the Cancertumors that are most likely to benefit from such combinatorial treatment .
24708484
BACKGROUND : Pre-operative chemoradiotherapy ( CRT ) is the standard treatment in clinical stage T3/4 or Cancernode positive rectal cancer .
24708484
Expression of Ki67 , TS , BAX , EpCAM , p53 , p21 , EGFR , CD44 , CD133 , CD166 , HIF1alpha and ALDH1 were assessed and correlated with Cancertumor regression grades and disease free survival .
24708484
Expression of Ki67 , TS , BAX , EpCAM , p53 , p21 , EGFR , CD44 , CD133 , CD166 , HIF1alpha and ALDH1 were assessed and correlated with tumor regression grades and Diseasedisease free survival .
24708484
In analyzing the associations between marker expressions and Cancertumor regression grades , high p21 expression at the pretreatment biopsy was significantly associated with non pCR ( p = 0.022 ) and poor disease free survival ( median DFS - low vs high p21 : 75.8 vs 58.1 months , p = 0.002 ) .
24708484
In analyzing the associations between marker expressions and tumor regression grades , high p21 expression at the pretreatment biopsy was significantly associated with non pCR ( p = 0.022 ) and Diseasepoor disease free survival ( median DFS - low vs high p21 : 75.8 vs 58.1 months , p = 0.002 ) .
24708484
CONCLUSION : These show high p21 and CD166 expression at the pretreatment biopsy were associated with Cancertumor regression and poor prognosis in patients treated with 5-FU based CRT .
24708484
CONCLUSION : These show high p21 and CD166 expression at the pretreatment biopsy were associated with tumor regression and AdverseOutcomepoor prognosis in patients treated with 5-FU based CRT .
24729716
PURPOSE : We performed this analysis to improve the understanding of the clinicopathological characteristics and clinical outcome of Cancernon small cell lung cancer ( NSCLC ) patients harboring the primary epidermal growth factor receptor ( EGFR ) T790M mutation along with activating EGFR mutation .
24729716
METHODS : CancerResected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR , as well as KRAS ( Kirsten rat sarcoma viral oncogene homolog ) , BRAF ( v-raf murine sarcoma viral oncogene homolog B ) , HER2 ( human epidermal growth factor 2 ) , PIK3CA ( phosphatidylinositol-4 ,5-bisphosphate 3-kinase , catalytic subunit alpha ) , and EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( anaplastic lymphoma receptor tyrosine kinase ) fusion .
24729716
METHODS : Resected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR , as well as KRAS ( CancerKirsten rat sarcoma viral oncogene homolog ) , BRAF ( v-raf murine sarcoma viral oncogene homolog B ) , HER2 ( human epidermal growth factor 2 ) , PIK3CA ( phosphatidylinositol-4 ,5-bisphosphate 3-kinase , catalytic subunit alpha ) , and EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( anaplastic lymphoma receptor tyrosine kinase ) fusion .
24729716
METHODS : Resected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR , as well as KRAS ( Kirsten rat sarcoma viral oncogene homolog ) , BRAF ( Cancerv-raf murine sarcoma viral oncogene homolog B ) , HER2 ( human epidermal growth factor 2 ) , PIK3CA ( phosphatidylinositol-4 ,5-bisphosphate 3-kinase , catalytic subunit alpha ) , and EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( anaplastic lymphoma receptor tyrosine kinase ) fusion .
24729716
METHODS : Resected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR , as well as KRAS ( Kirsten rat sarcoma viral oncogene homolog ) , BRAF ( v-raf murine sarcoma viral oncogene homolog B ) , HER2 ( human epidermal growth factor 2 ) , PIK3CA ( phosphatidylinositol-4 ,5-bisphosphate 3-kinase , catalytic subunit alpha ) , and EML4 ( echinoderm microtubule associated protein like 4 )-ALK ( Canceranaplastic lymphoma receptor tyrosine kinase ) fusion .
24729716
Clinical and pathological data , including sex , age at diagnosis , stage , Cancertumor differentiation , smoking history , histological subtype , relapse-free and overall survival , were further analyzed .
24729716
RESULTS : In all , 16 NSCLC patients were found to harbor primary EGFR T790M mutation , including 14 Canceradenocarcinomas and two adenosquamous carcinomas , accounting for 2.04 % of all the EGFR mutant cases and 0.84 % of the total .
24729716
RESULTS : In all , 16 NSCLC patients were found to harbor primary EGFR T790M mutation , including 14 adenocarcinomas and two Canceradenosquamous carcinomas , accounting for 2.04 % of all the EGFR mutant cases and 0.84 % of the total .
24735930
BACKGROUND : The clinical use of BRAF inhibitors for treatment of Cancermetastatic melanoma is limited by the development of drug resistance .
24735930
METHODS : Anti-tumor effects of the combination of the BRAF inhibitor ( BRAFi ) dabrafenib and GSK2141795B ( AKTi ) in a panel of 23 BRAF mutated Cancermelanoma cell lines were evaluated on growth inhibition by an ATP based luminescent assay , on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot .
24735930
CONCLUSIONS : AKTi combined with BRAFi based therapy may benefit patients with Cancertumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations .
24736073
We compared the clinical outcomes in gefitinib- and erlotinib treated patients harboring EGFR mutations who had recurrent or Cancermetastatic non-small-cell lung cancer ( NSCLC ) .
24736073
Most patients had Canceradenocarcinoma ( 98.3 % ) and good Eastern Cooperative Oncology Group performance status ( 0 , 1 ) ( 90.9 % ) .
24736073
The overall response rates and Diseasedisease control rates in the gefitinib- or erlotinib treated groups were 76.9 % versus 74.4 % ( p = 0.575 ) and 90.1 % versus 86.8 % , respectively ( p = 0.305 ) .
24740294
BACKGROUND : Previous studies have yielded conflicting results regarding the relationship between p53 status and response to chemotherapy in patients with Cancergastric cancer .
24740294
p53 positive status ( high expression of p53 protein and/or a mutant p53 gene ) was associated with improved response in Cancergastric cancer patients who received chemotherapy ( good response : risk ratio [ RR ] = 0.704 ; 95 % confidence intervals [ CI ] = 0.550-0 .903 ; P = 0.006 ) .
24740294
p53 positive status ( high expression of p53 protein and/or a mutant p53 gene ) was associated with improved response in gastric cancer patients who received chemotherapy ( good response : AdverseOutcomerisk ratio [ RR ] = 0.704 ; 95 % confidence intervals [ CI ] = 0.550-0 .903 ; P = 0.006 ) .
24740294
As five studies used neoadjuvant chemotherapy ( NCT ) and one used neoadjuvant chemoradiotherapy ( NCRT ) , we also analyzed these data , and found that p53 positive status was associated with a good response in Cancergastric cancer patients who received chemotherapy based neoadjuvant treatment ( RR = 0.675 , 95 % CI = 0.463-0 .985 ; P = 0.042 ) .
24740294
CONCLUSION : This meta-analysis indicated that p53 status may be a useful predictive biomarker for response to chemotherapy in Cancergastric cancer .
24740809
With intensified pediatric like therapy and Diseasegenetic disease dissection , the field of adult acute lymphoblastic leukemia ( ALL ) has evolved recently .
24740809
With intensified pediatric like therapy and genetic disease dissection , the field of Canceradult acute lymphoblastic leukemia ( ALL ) has evolved recently .
24740809
In this new context , we aimed to reassess the value of AdverseOutcomeconventional risk factors with regard to new genetic alterations and early response to therapy , as assessed by immunoglobulin and T-cell receptor minimal residual disease ( MRD ) levels .
24740809
In this new context , we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy , as assessed by immunoglobulin and DiseaseT-cell receptor minimal residual disease ( MRD ) levels .
24740809
In addition to AdverseOutcomeconventional risk factors , the most frequent currently available genetic alterations were included in the analysis .
24740809
These 2 factors allowed definition of a AdverseOutcomenew risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival .
24748501
BACKGROUND : CancerGastric carcinoma ( GC ) has one of the highest mortality rates of cancer diseases and has a high incidence rate in China .
24748501
BACKGROUND : Gastric carcinoma ( GC ) has one of the highest AdverseOutcomemortality rates of cancer diseases and has a high incidence rate in China .
24748501
BACKGROUND : Gastric carcinoma ( GC ) has one of the highest mortality rates of Cancercancer diseases and has a high incidence rate in China .
24748501
BACKGROUND : Gastric carcinoma ( GC ) has one of the highest mortality rates of Diseasecancer diseases and has a high incidence rate in China .
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Palliative chemotherapy is the main treatment for Canceradvanced gastric cancer .
24748501
It is necessary to compare the effectiveness and Diseasetoxicities of different regimens .
24748501
This study explores the possibility of methylation of DNA damage repair genes serving as a prognostic and chemo sensitive marker in Cancerhuman gastric cancer .
24748501
METHODS : The methylation status of five DNA damage repair genes ( CHFR , FANCF , MGMT , MLH1 , and RASSF1A ) was detected by nested methylation specific PCR in 102 Cancerparaffin embedded gastric cancer samples .
24748501
No association was found between methylation of CHFR , MLH1 , RASSF1A , MGMT , or FANCF with gender , age , Cancertumor size , tumor differentiation , lymph node metastasis , and TNM stage .
24748501
No association was found between methylation of CHFR , MLH1 , RASSF1A , MGMT , or FANCF with gender , age , tumor size , Cancertumor differentiation , lymph node metastasis , and TNM stage .
24748501
No association was found between methylation of CHFR , MLH1 , RASSF1A , MGMT , or FANCF with gender , age , tumor size , tumor differentiation , Cancerlymph node metastasis , and TNM stage .
24748501
In docetaxel treated Cancergastric cancer patients , resistance to docetaxel was found in CHFR unmethylated patients by Cox proportional hazards model ( HR 0.243 , 95 % CI , 0.069-0 .859 , p = 0.028 ) , and overall survival is longer in the CHFR methylated group compared with the CHFR unmethylated group ( log-rank , p = 0.036 ) .
24748501
In oxaliplatin treated Cancergastric cancer patients , resistance to oxaliplatin was found in MLH1 methylated patients ( HR 2.988 , 95 % CI , 1.064-8 .394 , p = 0.038 ) , and overall survival was longer in the MLH1 unmethylated group compared with the MLH1 methylated group ( log-rank , p = 0.046 ) .
24748501
CONCLUSIONS : CHFR is frequently methylated in Cancerhuman gastric cancer , and CHFR methylation may serve as a docetaxel sensitive marker .
24748501
MLH1 methylation was related to oxaliplatin resistance in Cancergastric cancer patients .
24758907
However , Cancerlung cancer patients are often with unknown EGFR mutation status because there are little tumor specimen to determine .
24758907
However , lung cancer patients are often with unknown EGFR mutation status because there are Cancerlittle tumor specimen to determine .
24758907
TKIs induce Cancertumor cell apoptosis which associates with several apoptosis related genes .
24758907
To explore the association between GNAS1 T393C polymorphism and therapeutic efficacy of TKI in Cancerpretreated advanced non small cell lung cancer ( NCSLC ) with unknown EGFR mutation status .
24758907
The Diseasedisease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype ( TT or CT ) ( 46.2 % vs 73.8 % , P = 0.039 ) .
24771645
PURPOSE : FGFR1 gene copy number ( GCN ) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor ( TKI ) response in Cancersquamous cell lung cancers ( SCC ) .
24771645
Herein , we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in Cancerlung cancer .
24771645
EXPERIMENTAL DESIGN : CancerHistologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity , a potent FGFR TKI .
24771645
A tissue microarray composed of Cancerresected lung tumors was submitted to FGFR1 GCN , and mRNA analyses and the results were validated with The Cancer Genome Atlas ( TCGA ) lung cancer data .
24771645
A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN , and mRNA analyses and the results were validated with The CancerCancer Genome Atlas ( TCGA ) lung cancer data .
24771645
A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN , and mRNA analyses and the results were validated with The Cancer Genome Atlas ( TCGA ) Cancerlung cancer data .
24771645
In Cancerresected tumors , 22 % of adenocarcinomas and 28 % of SCCs expressed high FGFR1 mRNA .
24771645
In resected tumors , 22 % of Canceradenocarcinomas and 28 % of SCCs expressed high FGFR1 mRNA .
24771645
CancerLung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations .
24771645
CONCLUSIONS : FGFR1 dependency is frequent across Cancervarious lung cancer histologies , and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN .
24771645
CONCLUSIONS : FGFR1 dependency is frequent across various lung cancer histologies , and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in Cancerlung cancer than FGFR1 GCN .
24771645
The study provides important and timely insight into clinical testing of FGFR TKIs in Cancerlung cancer and other solid tumor types .
24771645
The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and Cancerother solid tumor types .
24782778
Patients in whom the standard of care has failed or who have Canceruncommon tumors for which no standard of care exists are often treated with drugs selected based on the physician 's best guess .
24782778
With the advent of fast , Canceraffordable tumor profiling technologies , and a growth in the understanding of predictive biomarkers , it is now possible to identify drugs potentially associated with clinical benefit for such patients .
24782778
We present the Caris approach to evidence based Cancertumor profiling and two patients with advanced ovarian and prostate cancer in whom standard of care had failed and tumor profiling identified an effective treatment schedule .
24782778
We present the Caris approach to evidence based tumor profiling and two patients with advanced ovarian and Cancerprostate cancer in whom standard of care had failed and tumor profiling identified an effective treatment schedule .
24782778
We present the Caris approach to evidence based tumor profiling and two patients with advanced ovarian and prostate cancer in whom standard of care had failed and Cancertumor profiling identified an effective treatment schedule .
24782778
Worldwide , over 60,000 Cancercancer patients have undergone evidence based tumor profiling with CMI .
24782778
Worldwide , over 60,000 cancer patients have undergone evidence based Cancertumor profiling with CMI .
24793816
BACKGROUND : Patients with Diseaseprogressive disease after two or more HER2 directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options .
24793816
BACKGROUND : Patients with progressive disease after two or more HER2 directed regimens for recurrent or Cancermetastatic breast cancer have few effective therapeutic options .
24793816
Eligible patients ( > = 18 years , left ventricular ejection fraction > = 50 % , Eastern Cooperative Oncology Group performance status 0-2 ) with Cancerprogressive HER2 positive advanced breast cancer who had received two or more HER2 directed regimens in the advanced setting , including trastuzumab and lapatinib , and previous taxane therapy in any setting , were randomly assigned ( in a 2:1 ratio ) to trastuzumab emtansine ( 3.6 mg/kg intravenously every 21 days ) or physician 's choice using a permuted block randomisation scheme by an interactive voice and web response system .
24793816
Patients were stratified according to world region ( USA vs western Europe vs other ) , number of previous regimens ( excluding single-agent hormonal therapy ) for the treatment of Diseaseadvanced disease ( two to three vs more than three ) , and presence of visceral disease ( any vs none ) .
24793816
Patients were stratified according to world region ( USA vs western Europe vs other ) , number of previous regimens ( excluding single-agent hormonal therapy ) for the treatment of advanced disease ( two to three vs more than three ) , and presence of Diseasevisceral disease ( any vs none ) .
24793816
DiseaseNeutropenia ( ten [ 2 % ] vs 29 [ 16 % ] ) , diarrhoea ( three [ < 1 % ] vs eight [ 4 % ] ) , and febrile neutropenia ( one [ < 1 % ] vs seven [ 4 % ] ) were grade 3 or worse adverse events that were more common in the physician 's choice group than in the trastuzumab emtansine group .
24793816
Neutropenia ( ten [ 2 % ] vs 29 [ 16 % ] ) , diarrhoea ( three [ < 1 % ] vs eight [ 4 % ] ) , and Diseasefebrile neutropenia ( one [ < 1 % ] vs seven [ 4 % ] ) were grade 3 or worse adverse events that were more common in the physician 's choice group than in the trastuzumab emtansine group .
24793816
DiseaseThrombocytopenia ( 19 [ 5 % ] vs three [ 2 % ] ) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group .
24793816
INTERPRETATION : Trastuzumab emtansine should be considered as a new standard for patients with CancerHER2 positive advanced breast cancer who have previously received trastuzumab and lapatinib .
24797300
The outcome of patients with Canceracute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient related factors .
24797300
The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of Diseaseunfavorable disease characteristics and patient related factors .
24797300
The Diseasemain toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections , observed predominantly during the second induction cycle .
24797300
The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 Diseaseinfections , observed predominantly during the second induction cycle .
24797300
After restricting VPA to the first induction cycle and reducing the dose of idarubicin , these Diseasetoxicities dropped to rates observed in STANDARD .
24799460
BACKGROUND : The purpose of this article was to study the association of human papillomavirus ( HPV ) with clinical outcomes in patients with recurrent or Cancermetastatic squamous cell carcinoma of the head and neck ( SCCHN ) .
24799460
PATIENTS AND METHODS : CancerArchival baseline tumor specimens were obtained from patients treated on two clinical trials in recurrent or metastatic SCCHN : E1395 , a phase III trial of cisplatin and paclitaxel versus cisplatin and 5-fluorouracil , and E3301 , a phase II trial of irinotecan and docetaxel .
24799460
Eleven Cancertumors ( 17 % ) were HPV+ , 12 ( 18 % ) were p16+ , whereas 52 ( 80 % ) were both HPV- and p16-.
24799460
The other AdverseOutcomeunfavorable risk factor for OS was loss of > = 5 % weight in previous 6 months ( P = 0.0021 and 0.023 for HPV and p16 models , respectively ) .
24800185
BACKGROUND : Considering the high prevalence of female genital tract neoplasms , non specific nature of the initial symptoms , higher possibility of Cancermetastasis by the time of diagnosis , importance of differentiating metastatic Mullerian tumors or metastatic breast cancer in the female genital tract , especially in the ovary , and lack of diagnostic markers with high sensitivity and specificity , the purpose of the current study was to evaluate the utility of Paired box protein8 ( PAX8 ) expression in Mullerian and non Mullerian neoplasms .
24800185
BACKGROUND : Considering the high prevalence of female genital tract neoplasms , non specific nature of the initial symptoms , higher possibility of metastasis by the time of diagnosis , importance of differentiating Cancermetastatic Mullerian tumors or metastatic breast cancer in the female genital tract , especially in the ovary , and lack of diagnostic markers with high sensitivity and specificity , the purpose of the current study was to evaluate the utility of Paired box protein8 ( PAX8 ) expression in Mullerian and non Mullerian neoplasms .
24800185
BACKGROUND : Considering the high prevalence of female genital tract neoplasms , non specific nature of the initial symptoms , higher possibility of metastasis by the time of diagnosis , importance of differentiating metastatic Mullerian tumors or Cancermetastatic breast cancer in the female genital tract , especially in the ovary , and lack of diagnostic markers with high sensitivity and specificity , the purpose of the current study was to evaluate the utility of Paired box protein8 ( PAX8 ) expression in Mullerian and non Mullerian neoplasms .
24800185
MATERIALS AND METHODS : In this descriptive-analytic , cross-sectional study , paraffin embedded tissues of patients with definitive pathologic diagnosis of Mullerian and Cancernon Mullerian tumors were selected .
24800185
It was defined as the presence of nuclear staining in at least 10 % of the Cancertumor cell nuclei .
24800185
RESULTS : Thirty-seven Mullerian ( including 18 Cancerovarian epithelial tumors , 17 endometrial carcinoma and two endocervical adenocarcinoma ) and 37 non Mullerian tumors were studied for PAX8 expression .
24800185
RESULTS : Thirty-seven Mullerian ( including 18 ovarian epithelial tumors , 17 Cancerendometrial carcinoma and two endocervical adenocarcinoma ) and 37 non Mullerian tumors were studied for PAX8 expression .
24800185
RESULTS : Thirty-seven Mullerian ( including 18 ovarian epithelial tumors , 17 endometrial carcinoma and two Cancerendocervical adenocarcinoma ) and 37 non Mullerian tumors were studied for PAX8 expression .
24800185
RESULTS : Thirty-seven Mullerian ( including 18 ovarian epithelial tumors , 17 endometrial carcinoma and two endocervical adenocarcinoma ) and 37 Cancernon Mullerian tumors were studied for PAX8 expression .
24800185
Twenty-nine of 37 ( 78.4 % ) and one of 37 ( 2.7 % ) of the Mullerian and Cancernon Mullerian tumors were positive for PAX8 , respectively .
24800185
The sensitivity and specificity of PAX8 by IHC for differentiation of Mullerian from Cancernon Mullerian tumors was 78.4 % and 97.3 % , respectively .
24800185
CONCLUSION : Our findings indicated that PAX8 could be used as a useful IHC marker for diagnosing CancerMullerian tumors .
24800185
It has moderate to high sensitivity , but high specificity , for diagnosing Cancercarcinomas of Mullerian origin .
24801015
Diagnosis and classification of Canceracute myeloid leukemia ( AML ) are based on morphology and genetics .
24801015
An increasing number of gene mutations have been found , and some are used for AdverseOutcomerisk classification in AML patients with normal karyotype ( cytogenetically normal ( CN )-AML ) .
24836576
Translating whole-exome sequencing ( WES ) for prospective clinical use may have an impact on the care of patients with Cancercancer ; however , multiple innovations are necessary for clinical implementation .
24836576
These include rapid and robust WES of DNA derived from formalin fixed , Cancerparaffin embedded tumor tissue , analytical output similar to data from frozen samples and clinical interpretation of WES data for prospective use .
24836576
Here , we describe a prospective clinical WES platform for archival formalin fixed , Cancerparaffin embedded tumor samples .
24836576
Overall , this methodology may inform the widespread implementation of Cancerprecision cancer medicine .
24836762
TP53 mutations are found in 5-10 % of MDS and AML , where they are generally associated with complex karyotype and an overall AdverseOutcomepoor prognosis .
24836762
We analyzed TP53 mutations in 62 patients with AdverseOutcomehigh risk MDS or AML treated with AZA .
24836762
Thus , TP53 mutations strongly correlated with poorer survival in higher AdverseOutcomerisk MDS and AML treated with AZA .
24841718
Small-molecule inhibitors of poly ( ADP-ribose ) polymerase ( PARP ) have shown considerable promise in the treatment of homologous recombination ( CancerHR )-defective tumors , such as BRCA1- and BRCA2 deficient breast and ovarian cancers .
24841718
Small-molecule inhibitors of poly ( ADP-ribose ) polymerase ( PARP ) have shown considerable promise in the treatment of homologous recombination ( HR )-defective tumors , such as BRCA1- and BRCA2 deficient breast and Cancerovarian cancers .
24841718
We previously reported that Cancermantle cell lymphoma cells with deficiency in ataxia telangiectasia mutated ( ATM ) are sensitive to PARP-1 inhibitors in vitro and in vivo .
24841718
Here , we report that PARP inhibitors can potentially target ATM deficiency arising in a Cancersolid malignancy .
24841718
We show that ATM protein expression varies between Cancergastric cancer cell lines , with NUGC4 having significantly reduced protein levels .
24841718
Moreover , reducing ATM kinase activity using a small-molecule inhibitor ( KU55933 ) or shRNA mediated depletion of ATM protein enhanced olaparib sensitivity in Cancergastric cancer cell lines with depletion or inactivation of p53 .
24841718
Our results demonstrate that ATM is a potential predictive biomarker for PARP-1 inhibitor activity in Cancergastric cancer harboring disruption of p53 , and that combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARP-1 inhibitors to gastric cancer with p53 disruption .
24841718
Our results demonstrate that ATM is a potential predictive biomarker for PARP-1 inhibitor activity in gastric cancer harboring disruption of p53 , and that combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARP-1 inhibitors to Cancergastric cancer with p53 disruption .
24855211
Some studies have suggested that cases of Canceracute myeloid leukemia ( AML ) with low levels of FLT3 internal tandem duplications ( FLT3 ( ITD ) ) do not have a worse prognosis if there is a concomitant NPM1 mutation , although this is controversial .
24855211
If consolidation therapies are to be determined by relapse AdverseOutcomerisk , then NPM1 ( MUT ) cases with low-level FLT3 ( ITD ) should not be considered as good risk without further studies .
24855211
If consolidation therapies are to be determined by relapse risk , then NPM1 ( MUT ) cases with low-level FLT3 ( ITD ) should not be considered as AdverseOutcomegood risk without further studies .
24859829
Cytogenetically Cancernormal acute myeloid leukemia ( cn-AML ) is a group of heterogeneous diseases .
24859829
Cytogenetically normal acute myeloid leukemia ( cn-AML ) is a group of Diseaseheterogeneous diseases .
24859829
Gene mutations are increasingly used to assess the prognosis of cn-AML patients and guide AdverseOutcomerisk adapted treatment .
24868024
PURPOSE : In Asian countries , paclitaxel once per week is used as second-line treatment in Canceradvanced gastric cancer , including human epidermal growth factor receptor 2 ( HER2 ) -positive tumors .
24868024
PURPOSE : In Asian countries , paclitaxel once per week is used as second-line treatment in advanced gastric cancer , including human epidermal growth factor receptor 2 ( HER2 ) Cancer-positive tumors .
24868024
CONCLUSION : Lapatinib plus paclitaxel demonstrated activity in the second-line treatment of patients with CancerHER2 FISH positive IHC3+ advanced gastric cancer but did not significantly improve OS in the intent-to-treat population .
24868098
On May 14 , 2013 , the U.S. Food and Drug Administration approved erlotinib ( Tarceva , Astellas Pharma Inc. , Northbrook , IL , http://www.us.astellas.com/ ) for the first-line treatment of patients with Cancermetastatic non small cell lung cancer ( NSCLC ) whose tumors have epidermal growth factor receptor ( EGFR ) exon 19 deletions or exon 21 ( L858R ) substitution mutations .
24868098
On May 14 , 2013 , the U.S. Food and Drug Administration approved erlotinib ( Tarceva , Astellas Pharma Inc. , Northbrook , IL , http://www.us.astellas.com/ ) for the first-line treatment of patients with metastatic non small cell lung cancer ( NSCLC ) whose Cancertumors have epidermal growth factor receptor ( EGFR ) exon 19 deletions or exon 21 ( L858R ) substitution mutations .
24868098
The approval was based on clinically important improvements in progression-free survival ( PFS ) and objective response rate ( ORR ) and an Diseaseacceptable toxicity profile demonstrated in a multicenter , open label trial enrolling 174 patients with metastatic NSCLC whose tumors had EGFR mutations as determined by a laboratory developed test .
24868098
The approval was based on clinically important improvements in progression-free survival ( PFS ) and objective response rate ( ORR ) and an acceptable toxicity profile demonstrated in a multicenter , open label trial enrolling 174 patients with metastatic NSCLC whose Cancertumors had EGFR mutations as determined by a laboratory developed test .
24868098
The most frequent ( > = 30 % ) adverse reactions in the erlotinib treated patients were rash , diarrhea , Diseaseasthenia , cough , dyspnea , and decreased appetite .
24869598
BACKGROUND : Ibrutinib is an irreversible inhibitor of Bruton 's tyrosine kinase ( BTK ) and is effective in Cancerchronic lymphocytic leukemia ( CLL ) .
24869598
We evaluated patients with relapsed Diseasedisease to identify mutations that may mediate ibrutinib resistance .
24875859
CancerInflammatory myofibroblastic tumor ( IMT ) is a neoplasm that typically occurs in children .
24875859
The genetic landscape of this Cancertumor is incompletely understood and therapeutic options are limited .
24875859
Although 50 % of IMTs harbor Canceranaplastic lymphoma kinase ( ALK ) rearrangements , no therapeutic targets have been identified in ALK negative tumors .
24875859
Although 50 % of IMTs harbor anaplastic lymphoma kinase ( ALK ) rearrangements , no therapeutic targets have been identified in CancerALK negative tumors .
24875859
CancerMolecular tumor profiling revealed a ROS1 fusion , and he had a dramatic response to the ROS1 inhibitor crizotinib .
24875859
Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these Cancertumors to detect therapeutically actionable kinase fusions.SIGNIFICANCE : Our study describes the most comprehensive genomics based evaluation of IMT to date .
24875859
Because there is no " standard-of-care " therapy for IMT , the identification of actionable genomic alterations , in addition to ALK , is expected to redefine management strategies for patients with this Diseasedisease .
24893891
First generation EGFR tyrosine kinase inhibitors ( EGFR TKI ) provide significant clinical benefit in patients with advanced EGFR-mutant ( EGFRm ( + ) ) Cancernon small cell lung cancer ( NSCLC ) .
24893891
Patients ultimately develop Diseasedisease progression , often driven by acquisition of a second T790M EGFR TKI resistance mutation .
24893891
Preclinically , the drug potently inhibits signaling pathways and cellular growth in both EGFRm ( + ) and EGFRm ( + )/T790M ( + ) mutant cell lines in vitro , with lower activity against wild-type EGFR lines , translating into profound and Cancersustained tumor regression in EGFR-mutant tumor xenograft and transgenic models .
24893891
Preclinically , the drug potently inhibits signaling pathways and cellular growth in both EGFRm ( + ) and EGFRm ( + )/T790M ( + ) mutant cell lines in vitro , with lower activity against wild-type EGFR lines , translating into profound and sustained tumor regression in CancerEGFR-mutant tumor xenograft and transgenic models .
24894453
BACKGROUND : Inhibition of the activated epidermal growth factor receptor ( EGFR ) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab , is an effective modality of treatment for Cancermultiple human cancers .
24894453
Enzymatic EGFR inhibitors are effective for Cancerlung adenocarcinomas with somatic kinase domain EGFR mutations while , paradoxically , anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently .
24894453
Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while , paradoxically , anti-EGFR antibodies are more effective in colon and head and Cancerneck cancers where EGFR mutations occur less frequently .
24894453
In Cancercolorectal cancer , anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors .
24894453
In colorectal cancer , anti-EGFR antibodies are routinely used as second-line therapy of CancerKRAS wild-type tumors .
24894453
However , detailed mechanisms and genomic predictors for pharmacological response to these antibodies in Cancercolon cancer remain unclear .
24894453
FINDINGS : We describe a case of Cancercolorectal adenocarcinoma , which was found to harbor a kinase domain mutation , G724S , in EGFR through whole genome sequencing .
24894453
We show that G724S mutant EGFR is oncogenic and that it differs from Cancerclassic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro , yet relatively insensitive to small molecule kinase inhibitors .
24894453
Through biochemical and cellular pharmacologic studies , we have determined that cells harboring the Cancercolon cancer derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors .
24898067
BACKGROUND : HER-2 represents a relatively new therapeutic target for Cancernon small cell lung cancer ( NSCLC ) patients .
24898067
The activity of T-DM1 has been studied in Cancerbreast cancer but the role of T-DM1 in lung cancer remains unexplored .
24898067
The activity of T-DM1 has been studied in breast cancer but the role of T-DM1 in Cancerlung cancer remains unexplored .
24898067
Xenografted mice model has been generated using a NSCLC cell line to evaluate the effect of T-DM1 on Cancertumor growth .
24898067
Moreover , a morphometric and immunohistochemical analysis of Cancertumor xenografts was conducted .
24898067
In addition a correlation between cell density and Cancertumor size with both HER-2 expression and T-DM1 activity was established in vitro and in an in vivo xenograft model .
24898067
CONCLUSIONS : Our results indicate that targeting HER-2 with T-DM1 may offer a new therapeutic approach in CancerHER-2 over-expressing lung cancers including those resistant to EGFR TKIs .
24899684
The majority of Canceruveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11 , with consequent activation of the MAPK pathway .
24899684
Selective MEK inhibitors , such as selumetinib , have shown clinical benefit in Canceruveal melanoma .
24899684
Analysis of CancerMEK inhibitor resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity .
24899684
On the contrary , ectopic expression of DDX43 in Cancerparental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition .
24899684
We also analyzed the expression of DDX43 in liver metastases of patients with Canceruveal melanoma by RT-PCR , and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy .
24899684
The detection of DDX43 in patients with Canceruveal melanoma could lead to more targeted therapies for this disease .
24899684
The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this Diseasedisease .
24915778
BACKGROUND : Trametinib , an oral mitogen and extracellular signal related kinase ( MEK ) 1/2 inhibitor , holds promise for Cancermalignancies with rat sarcoma ( RAS ) mutations , like pancreas cancer .
24915778
BACKGROUND : Trametinib , an oral mitogen and extracellular signal related kinase ( MEK ) 1/2 inhibitor , holds promise for malignancies with Cancerrat sarcoma ( RAS ) mutations , like pancreas cancer .
24915778
BACKGROUND : Trametinib , an oral mitogen and extracellular signal related kinase ( MEK ) 1/2 inhibitor , holds promise for malignancies with rat sarcoma ( RAS ) mutations , like Cancerpancreas cancer .
24915778
This phase II study was designed to determine overall survival ( OS ) in patients with Cancerpancreas cancer treated with trametinib and gemcitabine .
24915778
METHODS : Adults with Canceruntreated metastatic adenocarcinoma of the pancreas were randomised ( 1:1 ) to receive intravenous gemcitabine 1000 mg/m ( 2 ) ( weekly x 7 for 8 weeks , then days 1 , 8 and 15 of 28-day cycles ) plus trametinib or placebo 2mg daily .
24915778
RAS mutations were determined in circulating free DNA ( cfDNA ) and Cancerarchival tumour tissue .
24915778
OS was evaluated in Cancerkirsten rat sarcoma viral oncogene homolog ( KRAS ) mutant and wild-type subgroups .
24915778
DiseaseThrombocytopenia , diarrhoea , rash and stomatitis were more frequent with trametinib , as was grade 3 anaemia .
24915778
Thrombocytopenia , diarrhoea , rash and Diseasestomatitis were more frequent with trametinib , as was grade 3 anaemia .
24915778
Thrombocytopenia , diarrhoea , rash and stomatitis were more frequent with trametinib , as was grade 3 Diseaseanaemia .
24915778
CONCLUSIONS : The addition of trametinib to gemcitabine did not improve OS , PFS , ORR or DOR in patients with previously Canceruntreated metastatic pancreas cancer .
24927325
AIM OF THE STUDY : To evaluate the frequency of MRE11/RAD50/NBS1 ( MRN )-complex loss of protein expression in Cancerendometrial cancers ( EC ) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly ( ADP-ribose ) polymerase ( PARP )-inhibitory treatment .
24927325
AIM OF THE STUDY : To evaluate the frequency of MRE11/RAD50/NBS1 ( MRN )-complex loss of protein expression in endometrial cancers ( EC ) and to determine whether loss of MRE11 renders the Cancercancer cells sensitive to Poly ( ADP-ribose ) polymerase ( PARP )-inhibitory treatment .
24927325
METHODS : MRN expression was examined in 521 samples of Cancerendometrial carcinomas and in 10 cancer cell lines .
24927325
METHODS : MRN expression was examined in 521 samples of endometrial carcinomas and in 10 Cancercancer cell lines .
24927325
RESULTS : Loss of MRE11 protein was found in 30.7 % of CancerEC tumours and significantly associated with loss of RAD50 , NBS1 and mismatch repair protein expression .
24927407
Owing to the more recent positive results with the anti-CD33 immunotoxin gemtuzumab ozogamicin , therapy against Canceracute myeloid leukemias ( AMLs ) targeting CD33 holds many promises .
24927407
In addition , blasts of patients with mutant nucleophosmin ( NPM1 ) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of Diseaseminimal residual disease guided interventions in mutated NPM1 positive AMLs .
24938562
IMPORTANCE : CancerUveal melanoma is characterized by mutations in GNAQ and GNA11 , resulting in mitogen activated protein kinase pathway activation .
24938562
OBJECTIVE : To assess the efficacy of selumetinib , a selective , non adenosine triphosphate competitive inhibitor of MEK1 and MEK2 , in Canceruveal melanoma .
24938562
DESIGN , SETTING , AND PARTICIPANTS : Randomized , open-label , phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with Cancermetastatic uveal melanoma at 15 academic oncology centers in the United States and Canada .
24938562
INTERVENTIONS : One hundred one patients were randomized in a 1:1 ratio to receive selumetinib , 75 mg orally twice daily on a continual basis ( n = 50 ) , or chemotherapy ( temozolomide , 150 mg/m2 orally daily for 5 of every 28 days , or dacarbazine , 1000 mg/m2 intravenously every 21 days [ investigator choice ] ; n = 51 ) until Diseasedisease progression , death , intolerable adverse effects , or withdrawal of consent .
24938562
Additional end points , including overall survival , response rate , and safety and Diseasetoxicity , were assessed as of December 31 , 2013 .
24938562
Forty-nine percent of patients treated with selumetinib achieved Cancertumor regression , with 14 % achieving an objective radiographic response to therapy .
24938562
CONCLUSIONS AND RELEVANCE : In this hypothesis generating study of patients with Canceradvanced uveal melanoma , selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate ; however , no improvement in overall survival was observed .
24943832
Through the European Research Initiative on Cancerchronic lymphocytic leukemia ( CLL ) ( ERIC ) , we screened 3490 patients with CLL for mutations within the NOTCH1 ( n = 3334 ) , SF3B1 ( n = 2322 ) , TP53 ( n = 2309 ) , MYD88 ( n = 1080 ) and BIRC3 ( n = 919 ) genes , mainly at diagnosis ( 75 % ) and before treatment ( > 90 % ) .
24947927
PURPOSE : This phase I expansion study assessed safety , pharmacodynamic effects , and antitumor activity of RO4987655 , a pure MEK inhibitor , in selected patients with Canceradvanced solid tumor .
24947927
Here , we present the part 2 expansion that included Cancermelanoma , non small cell lung cancer ( NSCLC ) , and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease ( PD ) .
24947927
Here , we present the part 2 expansion that included melanoma , Cancernon small cell lung cancer ( NSCLC ) , and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease ( PD ) .
24947927
Here , we present the part 2 expansion that included melanoma , non small cell lung cancer ( NSCLC ) , and Cancercolorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease ( PD ) .
24947927
Here , we present the part 2 expansion that included melanoma , non small cell lung cancer ( NSCLC ) , and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until Diseaseprogressive disease ( PD ) .
24947927
CancerSequential tumor sampling investigated multiple markers of pathway activation and tumor effects , including ERK phosphorylation and Ki-67 expression .
24947927
Sequential tumor sampling investigated multiple markers of pathway activation and Cancertumor effects , including ERK phosphorylation and Ki-67 expression .
24947927
BRAF and KRAS testing were implemented as selection criteria and Cancerbroader tumor mutational analysis added .
24947927
RESULTS : Ninety-five patients received RO4987655 , including 18 CancerBRAF-mutant melanoma , 23 BRAF wild-type melanoma , 24 KRAS-mutant NSCLC , and 30 KRAS-mutant colorectal cancer .
24947927
RESULTS : Ninety-five patients received RO4987655 , including 18 BRAF-mutant melanoma , 23 CancerBRAF wild-type melanoma , 24 KRAS-mutant NSCLC , and 30 KRAS-mutant colorectal cancer .
24947927
RESULTS : Ninety-five patients received RO4987655 , including 18 BRAF-mutant melanoma , 23 BRAF wild-type melanoma , 24 KRAS-mutant NSCLC , and 30 CancerKRAS-mutant colorectal cancer .
24947927
Most frequent adverse events were rash , Diseaseacneiform dermatitis , and gastrointestinal disorders , mostly grade 1/2 .
24947927
Most frequent adverse events were rash , acneiform dermatitis , and Diseasegastrointestinal disorders , mostly grade 1/2 .
24947927
Four ( 24 % ) of 17 BRAF mutated Cancermelanoma had partial response as did four ( 20 % ) of 20 BRAF wild-type melanoma and two ( 11 % ) of 18 KRAS-mutant NSCLC .
24947927
Four ( 24 % ) of 17 BRAF mutated melanoma had partial response as did four ( 20 % ) of 20 CancerBRAF wild-type melanoma and two ( 11 % ) of 18 KRAS-mutant NSCLC .
24947927
All CancerKRAS-mutant colorectal cancer developed PD .
24947927
CancerPaired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation .
24947927
Detailed mutational profiling confirmed RAS and RAF screening and identified additional aberrations ( NRAS and Cancernon-BRAF melanomas ; PIK3CA and KRAS colorectal cancer ) without therapeutic implications .
24947927
Detailed mutational profiling confirmed RAS and RAF screening and identified additional aberrations ( NRAS and non-BRAF melanomas ; PIK3CA and CancerKRAS colorectal cancer ) without therapeutic implications .
24947927
Single-agent activity was observed in all entities except Cancercolorectal cancer .
24950457
Effective targeted therapy strategies are still lacking for the 15-20 % of Cancermelanoma patients whose melanomas are driven by oncogenic NRAS .
24950457
Effective targeted therapy strategies are still lacking for the 15-20 % of melanoma patients whose Cancermelanomas are driven by oncogenic NRAS .
24950457
An analysis of BRAF-mutant and CancerNRAS-mutant melanoma cell lines showed the NRAS-mutant cohort to be enriched for targets of amuvatinib , including Axl , c-KIT , and the Axl ligand Gas6 .
24950457
Increasing concentrations of amuvatinib selectively inhibited the growth of NRAS-mutant , but not CancerBRAF-mutant melanoma cell lines , an effect associated with induction of S-phase and G2/M-phase cell cycle arrest and induction of apoptosis .
24950457
In three-dimensional cell culture experiments , amuvatinib was cytotoxic against CancerNRAS-mutant melanoma cell lines .
24950457
Thus , we show for the first time that amuvatinib has proapoptotic activity against Cancermelanoma cell lines , with selectivity observed for those harboring oncogenic NRAS .
24957073
In this updated analysis of the EXPERT-C trial we show that , in magnetic resonance imaging defined , high-risk , locally advanced Cancerrectal cancer , adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy , surgery , and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival ( PFS ) and overall survival ( OS ) in both KRAS and BRAF wild-type and unselected patients .
24961465
Survivin expression is highly correlated with Canceradvanced non small cell lung cancer ( NSCLC ) and poor prognosis .
24961465
Survivin expression is highly correlated with advanced non small cell lung cancer ( NSCLC ) and AdverseOutcomepoor prognosis .
24961465
In this retrospective study of banked pathology tissue of patients with advanced NSCLC , we tested for correlations of N-survivin expression in Cancertumor tissues and responsiveness to treatment with platinum based regimens containing paclitaxel or docetaxel .
24961465
Patients with Cancerhigh tumor N-survivin expression had significantly better responses to taxane-platinum chemotherapy than those with low tumor N-survivin expression ( P < 0.001 ) .
24961465
Patients with high tumor N-survivin expression had significantly better responses to taxane-platinum chemotherapy than those with Cancerlow tumor N-survivin expression ( P < 0.001 ) .
24961465
Adjusted multivariate modeling found Cancerhigh tumor N-survivin expression to be an independent prognostic factor for a clinical response to chemotherapy ( high vs. low , OR 6.14 , 95 % CI 1.62-23 .29 ; P = 0.008 ) .
24961465
Median overall survival differed significantly between those with Cancerhigh tumor N-survivin expression who did and did not respond to chemotherapy and between those with low tumor N-survivin expression who did and did not respond to chemotherapy ( P < 0.05 ) .
24961465
Median overall survival differed significantly between those with high tumor N-survivin expression who did and did not respond to chemotherapy and between those with Cancerlow tumor N-survivin expression who did and did not respond to chemotherapy ( P < 0.05 ) .
24961465
CancerTumor N-survivin expression shows promise as a predictive biomarker in the chemotherapy setting as a surrogate marker of high proliferation status .
24962318
CancerMelanoma is a devastating form of skin cancer with limited therapeutic options .
24962318
Melanoma is a devastating form of Cancerskin cancer with limited therapeutic options .
24962318
Fifteen to 20 % of patients with Cancermelanoma have an activating mutation in the GTPase , NRAS .
24962318
Whereas many studies have analyzed RAF and PI3K signaling in Cancermutant NRAS melanoma , the role of RalGEF and Ral is understudied and TBK1 has not been examined .
24962318
In Cancermelanoma , NRAS overexpression increased TBK1 phosphorylation .
24962318
This effect was absent in Cancermelanoma cells that are wild-type for NRAS .
24962318
These results suggest the utility of TBK1 inhibitors as part of a treatment regimen for patients with Cancermutant NRAS melanoma , for whom there are no current effective therapies.IMPLICATIONS : TBK1 promotes the malignant properties of NRAS-mutant melanoma and its targeting , in combination with MEK , promotes apoptosis , thus providing a potential novel targeted therapeutic option .
24962318
These results suggest the utility of TBK1 inhibitors as part of a treatment regimen for patients with mutant NRAS melanoma , for whom there are no current effective therapies.IMPLICATIONS : TBK1 promotes the malignant properties of CancerNRAS-mutant melanoma and its targeting , in combination with MEK , promotes apoptosis , thus providing a potential novel targeted therapeutic option .
24981688
Activating internal tandem duplication ( ITD ) mutations in the fms like tyrosine kinase 3 ( FLT3 ) gene ( FLT3-ITD ) are associated with AdverseOutcomepoor outcome in acute myeloid leukemia , but their prognostic impact in acute promyelocytic leukemia ( APL ) remains controversial .
24981688
Activating internal tandem duplication ( ITD ) mutations in the fms like tyrosine kinase 3 ( FLT3 ) gene ( FLT3-ITD ) are associated with poor outcome in Canceracute myeloid leukemia , but their prognostic impact in acute promyelocytic leukemia ( APL ) remains controversial .
24981688
Activating internal tandem duplication ( ITD ) mutations in the fms like tyrosine kinase 3 ( FLT3 ) gene ( FLT3-ITD ) are associated with poor outcome in acute myeloid leukemia , but their prognostic impact in Canceracute promyelocytic leukemia ( APL ) remains controversial .
24987354
CONTEXT : For patients with Cancermetastatic papillary thyroid carcinoma ( PTC ) refractory to radioactive iodine ( RAI ) treatment , systemic chemotherapy has limited efficacy .
24987354
CancerSuch tumors frequently harbor BRAF V600E , and this alteration may predict responsiveness to vemurafenib treatment .
24987354
DESIGN : Hybridization capture of 3,769 exons of 236 Cancercancer related genes and the introns of 19 genes frequently rearranged in cancer was applied to > 50 ng of DNA extracted from a formalin fixed , paraffin embedded biopsy of a lymph node containing metastatic PTC and was sequenced to a high , uniform coverage of x616 .
24987354
DESIGN : Hybridization capture of 3,769 exons of 236 cancer related genes and the introns of 19 genes frequently rearranged in Cancercancer was applied to > 50 ng of DNA extracted from a formalin fixed , paraffin embedded biopsy of a lymph node containing metastatic PTC and was sequenced to a high , uniform coverage of x616 .
24987354
RESULTS : A BRAF V600E alteration was identified with no other somatic genomic alterations present within a Cancernear diploid tumor genome .
24989892
Patients with CancerHER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared with patients treated with chemotherapy alone .
25002028
Activation of the phosphoinositide 3-kinase ( PI3K ) pathway occurs frequently in Cancerbreast cancer .
25002028
A combinatorial drug screen on Cancermultiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI 3K inhibition synergistically reduces cell viability .
25002028
Laboratory studies revealed that Cancersensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so .
25002028
Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but Cancercancers with reduced sensitivity fail to do so .
25002028
Similarly , patients ' Cancertumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB , while nonresponding tumors showed sustained or increased levels of pRB .
25002028
Similarly , patients ' tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB , while Cancernonresponding tumors showed sustained or increased levels of pRB .
25002028
Importantly , the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to Cancertumor regressions in PIK3CA mutant xenografts .
25010864
BACKGROUND : Chemotherapy response in Cancerovarian cancer patients is frequently compromised by drug resistance , possibly due to altered drug metabolism .
25010864
Platinum drugs are metabolised by glutathione S-transferase P1 ( GSTP1 ) , which is abundantly , but variably expressed in Cancerovarian tumours .
25010864
We have created Cancernovel ovarian tumour cell line models to investigate the extent to which differential GSTP1 expression influences chemosensitivity .
25010864
METHODS : Glutathione S-transferase P1 was stably deleted in A2780 and expression significantly reduced in cisplatin resistant A2780DPP cells using Mission shRNA constructs , and MTT assays used to compare chemosensitivity to chemotherapy drugs used to treat Cancerovarian cancer .
25010864
CONCLUSIONS : Glutathione S-transferase P1 has an important role in cisplatin and carboplatin metabolism in Cancerovarian cancer cells .
25010864
Inter-tumour differences in GSTP1 expression may therefore influence response to platinum based chemotherapy in Cancerovarian cancer patients .
25014773
CCAAT and enhancer binding protein alpha ( CEBPA ) mutations are a favorable prognostic factor in Canceradult acute myeloid leukemia ( AML ) patients ; however , few studies have examined their significance in pediatric AML patients .
25014773
These results suggest that CEBPA mutations , particularly CEBPA-double , are an independent favorable prognostic factor in pediatric AML patients , which will have important implications for AdverseOutcomerisk stratified therapy .
25015329
We investigated the presence of KIT ( M541L ) in five males with Cancerchronic eosinophilic leukemia , not otherwise specified ( CEL , NOS ) , all negative for Platelet derived growth factor-alpha ( PDGFR ) or PDGFRbeta abnormalities , which responded to imatinib therapy .
25024077
PURPOSE : To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5 :1,295,228 C > T ( C228T ) , individually and in their coexistence , in Cancerpapillary thyroid cancer ( PTC ) .
25024077
CancerTumor recurrence rates were 25.8 % ( 50 of 194 ; 77.60 recurrences per 1,000 person-years ; 95 % CI , 58.81 to 102.38 ) versus 9.6 % ( 30 of 313 ; 22.88 recurrences per 1,000 person-years ; 95 % CI , 16.00 to 32.72 ) in BRAF mutation positive versus -negative patients ( hazard ratio [ HR ] , 3.22 ; 95 % CI , 2.05 to 5.07 ) and 47.5 % ( 29 of 61 ; 108.55 recurrences per 1,000 person-years ; 95 % CI , 75.43 to 156.20 ) versus 11.4 % ( 51 of 446 ; 30.21 recurrences per 1,000 person-years ; 95 % CI , 22.96 to 39.74 ) in TERT mutation positive versus -negative patients ( HR , 3.46 ; 95 % CI , 2.19 to 5.45 ) .
25037629
Janus kinase 2 ( JAK2 ) mutations define Diseasepolycythemia vera ( PV ) .
25037629
Calreticulin ( CALR ) and Cancermyeloproliferative leukemia virus oncogene ( MPL ) mutations are specific to JAK2 unmutated essential thrombocythemia ( ET ) and primary myelofibrosis ( PMF ) .
25037629
Calreticulin ( CALR ) and myeloproliferative leukemia virus oncogene ( MPL ) mutations are specific to DiseaseJAK2 unmutated essential thrombocythemia ( ET ) and primary myelofibrosis ( PMF ) .
25037629
We examined the effect of these mutations on Diseaselong-term disease outcome .
25056119
Following mutations in BRAF and NRAS , the RAC1 c. 85C > T single-nucleotide variant ( SNV ) encoding P29S amino acid change represents the next most frequently observed protein coding hotspot mutation in Cancermelanoma .
25056119
Here , we demonstrate that Cancermelanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors ( vemurafenib and dabrafenib ) .
25056119
Enforced expression of RAC1 P29S in Cancersensitive BRAF-mutant melanoma cell lines confers resistance manifested by increased viability , decreased apoptosis , and enhanced tumor growth in vivo upon treatment with RAF inhibitors .
25056119
Enforced expression of RAC1 P29S in sensitive BRAF-mutant melanoma cell lines confers resistance manifested by increased viability , decreased apoptosis , and enhanced Cancertumor growth in vivo upon treatment with RAF inhibitors .
25056119
Conversely , RNAi mediated silencing of endogenous RAC1 P29S in a Cancermelanoma cell line with a co-occurring BRAF V600 mutation increased sensitivity to vemurafenib and dabrafenib .
25056119
Our results suggest RAC1 P29S status may offer a predictive biomarker for RAF inhibitor resistance in Cancermelanoma patients , where it should be evaluated clinically .
25081901
BACKGROUND : A germline mutation in the 3 '-untranslated region of KRAS ( rs61764370 , KRAS-variant : TG/GG ) has previously been associated with altered patient outcome and drug resistance and sensitivity in Cancervarious cancers .
25081901
We examined the prognostic and predictive significance of this variant in recurrent and metastatic ( R/M ) head and Cancerneck squamous cell carcinoma ( HNSCC ) .
25081901
p16 expression was determined in a subset of 26 Canceroropharynx tumors by immunohistochemistry .
25081901
Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and Cancernon variant tumors .
25081901
RESULTS : KRAS-variant status was determined in 95/103 ( 92 % ) of the CancerHNSCC tumor samples and the allelic frequency of TG/GG was 32 % ( 30/95 ) .
25081901
Conversely , KRAS-variant patients appeared to experience some improvement in Diseasedisease control when cetuximab was added to their platinum based regimen ( log-rank P = 0.04 ) .
25082261
BACKGROUND : Platinum based chemotherapy improves survival among patients with Cancernon small cell lung cancer ( NSCLC ) , but the efficiency is limited due to resistance .
25082261
RESULTS : Aurora-A expression was significantly associated with clinical stage ( p = 0.018 ) , Cancerlymph node metastasis ( p = 0.038 ) and recurrence ( p = 0.005 ) , and was an independent prognostic parameter in multivariate analysis .
25082261
In vitro data showed that Aurora-A expression was elevated in Cancercisplatin resistant lung cancer cells , and overexpression or knockdown of Aurora-A resulted in increased or decreased cellular resistance to cisplatin .
25086725
FGFR1 amplification has been identified recently as an important therapeutic target in Cancernon-small-cell lung cancer ( NSCLC ) , particularly squamous cell carcinoma ( SqCC ) .
25086725
FGFR1 amplification has been identified recently as an important therapeutic target in non-small-cell lung cancer ( NSCLC ) , particularly Cancersquamous cell carcinoma ( SqCC ) .
25086725
FGFR1 amplification was found in 32/369 ( 8.7 % ) of NSCLC and was more frequent in SqCC ( 18.0 % in SqCC , 3.0 % in Canceradenocarcinoma ; p < 0.001 ) and in smokers ( p < 0.001 ) .
25086725
These results suggest that FGFR1 amplification is associated with smoking history and Cancersquamous cell carcinoma histology and might indicate poor prognosis .
25086725
These results suggest that FGFR1 amplification is associated with smoking history and squamous cell carcinoma histology and might indicate AdverseOutcomepoor prognosis .
25089570
Schlafen-11 ( SLFN11 ) showed a highly significant positive correlation with the response of topoisomerase inhibitors in Cancercancer cell lines derived from prostate , lung , etc. .
25089570
However , this finding has not been validated in Cancercolorectal cancers ( CRCs ) .
25111426
DiseaseLynch syndrome ( LS ) is caused by germline mutations in mismatch repair ( MMR ) genes , resulting in microsatellite-unstable tumours .
25111426
Lynch syndrome ( LS ) is caused by germline mutations in mismatch repair ( MMR ) genes , resulting in Cancermicrosatellite-unstable tumours .
25111426
The aim of this study was to investigate somatic MMR gene aberrations in microsatellite-unstable colorectal and Cancerendometrial cancers of sLS patients negative for germline MMR gene mutations .
25111426
In total , Cancermicrosatellite-unstable tumours of 40 sLS patients ( male and female 20/20 , median age 57 years ) were screened for somatic MMR gene mutations by next generation sequencing .
25111426
In addition , loss of heterozygosity ( LOH ) of the affected MMR genes in these Cancertumours as well as in 68 LS associated tumours and 27 microsatellite-unstable tumours with MLH1 promoter hypermethylation was studied .
25111426
In addition , loss of heterozygosity ( LOH ) of the affected MMR genes in these tumours as well as in 68 LS associated Cancertumours and 27 microsatellite-unstable tumours with MLH1 promoter hypermethylation was studied .
25111426
In addition , loss of heterozygosity ( LOH ) of the affected MMR genes in these tumours as well as in 68 LS associated tumours and 27 Cancermicrosatellite-unstable tumours with MLH1 promoter hypermethylation was studied .
25111426
Of the sLS cases , 5/40 ( 13 % ) Cancertumours had two pathogenic somatic mutations and 16/40 ( 40 % ) tumours had a ( likely ) pathogenic mutation and LOH .
25111426
Of the sLS cases , 5/40 ( 13 % ) tumours had two pathogenic somatic mutations and 16/40 ( 40 % ) Cancertumours had a ( likely ) pathogenic mutation and LOH .
25111426
Overall , LOH of the affected MMR gene locus was observed in 24/39 ( 62 % ) Cancertumours with informative LOH markers .
25111426
Of the LS cases and the Cancertumours with MLH1 promoter hypermethylation , 39/61 ( 64 % ) and 2/21 ( 10 % ) tumours , respectively , demonstrated LOH .
25111426
Of the LS cases and the tumours with MLH1 promoter hypermethylation , 39/61 ( 64 % ) and 2/21 ( 10 % ) Cancertumours , respectively , demonstrated LOH .
25111426
Half of Cancermicrosatellite-unstable tumours of sLS patients without germline MMR gene mutations had two ( likely ) deleterious somatic MMR gene aberrations , indicating their sporadic origin .
25121551
Two promoter mutations , chr5 :1295228 C > T and chr5 :1295250 C > T , in the gene for telomerase reverse transcriptase ( TERT ) have been recently identified in Cancerthyroid cancers and shown to be important in thyroid tumor pathogenesis .
25121551
Two promoter mutations , chr5 :1295228 C > T and chr5 :1295250 C > T , in the gene for telomerase reverse transcriptase ( TERT ) have been recently identified in thyroid cancers and shown to be important in Cancerthyroid tumor pathogenesis .
25121551
We found TERT promoter mutations in 0.0 % ( 0/179 ) of benign thyroid nodules and 7.0 % ( 9/129 ) of thyroid nodules of differentiated Cancerthyroid cancer , representing a 100 % diagnostic specificity and 7.0 % sensitivity , with the latter rising to 38.0 % ( 49/129 ) when combined with BRAF V600E testing .
25121551
Approximately 80 % of the TERT promoter mutation positive thyroid nodules were Cancerthyroid cancers with aggressive clinicopathological behaviors , such as extrathyroidal invasion , lymph node metastases , distant metastases , disease recurrence or patient death .
25121551
Approximately 80 % of the TERT promoter mutation positive thyroid nodules were thyroid cancers with aggressive clinicopathological behaviors , such as extrathyroidal invasion , lymph node metastases , distant metastases , Diseasedisease recurrence or patient death .
25121551
Thus , a positive TERT promoter mutation test not only definitively diagnoses a thyroid nodule as cancerous but also preoperatively identifies a Cancercancer with aggressive potential .
25121551
This is the first study , to our knowledge , of TERT promoter mutations on thyroid FNAB , demonstrating the value of this novel molecular testing in the diagnosis of thyroid nodules and AdverseOutcomepreoperative risk stratification of thyroid cancer .
25121551
This is the first study , to our knowledge , of TERT promoter mutations on thyroid FNAB , demonstrating the value of this novel molecular testing in the diagnosis of thyroid nodules and preoperative risk stratification of Cancerthyroid cancer .
25121551
Thus , testing of TERT promoter mutations on FNAB will enhance and improve the current molecular based approaches to the management of thyroid nodules and Cancerthyroid cancer .
25153538
BACKGROUND : Patients with Cancernon-small-cell lung cancer ( NSCLC ) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib .
25153538
We used Response Evaluation Criteria in CancerSolid Tumors criteria ( version 1.1 ) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan ( CT or MRI ) , with central radiological review of individuals with brain metastases .
25153538
Dose limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day ; one individual had grade 3 headache and the other had grade 3 Diseaseneutropenia .
25153538
The most common grade 3-4 adverse events were increased levels of gamma-glutamyl transpeptidase ( two [ 4 % ] ) , a reduction in the number of neutrophils ( two [ 4 % ] ) , and Diseasehypophosphataemia ( two [ 4 % ] ) .
25153538
Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib : acute renal failure ; pleural effusion and pericardial effusion ; and Cancerbrain metastasis .
25153538
16 ( 36 % ) patients had Diseasestable disease ; the remaining four ( 9 % ) had progressive disease .
25153538
16 ( 36 % ) patients had stable disease ; the remaining four ( 9 % ) had Diseaseprogressive disease .
25153538
Of 21 patients with CNS metastases at baseline , 11 ( 52 % ) had an objective response ; six ( 29 % ) had a complete response ( three unconfirmed ) and five ( 24 % ) had a partial response ( one unconfirmed ) ; eight ( 38 % ) patients had Diseasestable disease and the remaining two ( 10 % ) had progressive disease .
25153538
Of 21 patients with CNS metastases at baseline , 11 ( 52 % ) had an objective response ; six ( 29 % ) had a complete response ( three unconfirmed ) and five ( 24 % ) had a partial response ( one unconfirmed ) ; eight ( 38 % ) patients had stable disease and the remaining two ( 10 % ) had Diseaseprogressive disease .
25153719
The role of HER4 in Cancerbreast cancer is controversial and its role in relation to trastuzumab resistance remains unclear .
25153719
However , knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in CancerHER2 positive breast cancer cells .
25153719
There was also increased nuclear HER4 staining in the Cancertumours from BT474 xenograft mice and human patients treated with trastuzumab .
25153719
Furthermore , nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in CancerHER2 positive breast cancer .
25153719
Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in CancerHER2 positive breast cancer .
25153719
Therefore , our study provides novel findings that HER4 activation , cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in CancerHER2 positive breast cancer .
25153719
Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in CancerHER2 positive breast cancer .
25171497
BACKGROUND : Fibroblast growth factor receptor ( FGFR ) gene amplification has been reported in different types of Cancercancer .
25171497
We performed an up-to-date meta-analysis to further characterize the prognostic value of FGFR gene amplification in patients with Cancercancer .
25171497
METHODS : A search of several databases , including MEDLINE ( PubMed ) , EMBASE , Web of Science , and China National Knowledge Infrastructure , was conducted to identify studies examining the association between FGFR gene amplification and Cancercancer .
25171497
A total of 24 studies met the inclusion criteria , and overall incidence rates , hazard AdverseOutcomerisk ( HR ) , overall survival , disease-free survival , and 95 % confidence intervals ( CIs ) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included studies .
25171497
CONCLUSIONS : Current evidence supports the conclusion that the outcomes of patients with FGFR gene amplified Cancercancers is worse than for those with non FGFR gene amplified cancers .
25171497
CONCLUSIONS : Current evidence supports the conclusion that the outcomes of patients with FGFR gene amplified cancers is worse than for those with non FGFR gene amplified Cancercancers .
25184630
We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA ( AR-V7 ) in circulating Cancertumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone .
25184630
We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA ( AR-V7 ) in circulating tumor cells from men with Canceradvanced prostate cancer would be associated with resistance to enzalutamide and abiraterone .
25184630
METHODS : We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating Cancertumor cells from prospectively enrolled patients with metastatic castration resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone .
25184630
METHODS : We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with Cancermetastatic castration resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone .
25184630
RESULTS : A total of 31 enzalutamide treated patients and 31 abiraterone treated patients were enrolled , of whom 39 % and 19 % , respectively , had detectable AR-V7 in circulating Cancertumor cells .
25184630
CONCLUSIONS : Detection of AR-V7 in circulating Cancertumor cells from patients with castration resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone .
25184630
CONCLUSIONS : Detection of AR-V7 in circulating tumor cells from patients with Cancercastration resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone .
25186949
CancerPediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors , representing a paradigm for studying cancers driven by transcription factor rearrangements .
25186949
Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors , representing a paradigm for studying Cancercancers driven by transcription factor rearrangements .
25186949
In this study , we describe the somatic landscape of Cancerpediatric Ewing sarcoma .
25186949
These Cancertumors are among the most genetically normal cancers characterized to date , with only EWS-ETS rearrangements identified in the majority of tumors .
25186949
These tumors are among the most genetically Cancernormal cancers characterized to date , with only EWS-ETS rearrangements identified in the majority of tumors .
25186949
These tumors are among the most genetically normal cancers characterized to date , with only EWS-ETS rearrangements identified in the majority of Cancertumors .
25186949
STAG2 loss , however , is present in more than 15 % of CancerEwing sarcoma tumors ; occurs by point mutation , rearrangement , and likely nongenetic mechanisms ; and is associated with disease dissemination .
25186949
STAG2 loss , however , is present in more than 15 % of Ewing sarcoma tumors ; occurs by point mutation , rearrangement , and likely nongenetic mechanisms ; and is associated with Diseasedisease dissemination .
25186949
Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways , highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease.SIGNIFICANCE : We performed next generation sequencing of CancerEwing sarcoma , a pediatric cancer involving bone , characterized by expression of EWS-ETS fusions .
25186949
Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways , highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease.SIGNIFICANCE : We performed next generation sequencing of Ewing sarcoma , a Cancerpediatric cancer involving bone , characterized by expression of EWS-ETS fusions .
25186949
However , we discovered that loss of STAG2 expression occurs in 15 % of Cancertumors and is associated with metastatic disease , suggesting a potential genetic vulnerability in Ewing sarcoma .
25186949
However , we discovered that loss of STAG2 expression occurs in 15 % of tumors and is associated with Diseasemetastatic disease , suggesting a potential genetic vulnerability in Ewing sarcoma .
25186949
However , we discovered that loss of STAG2 expression occurs in 15 % of tumors and is associated with metastatic disease , suggesting a potential genetic vulnerability in CancerEwing sarcoma .
25199829
KRAS is the most frequently mutated oncogene in Cancerhuman cancer , yet no therapies are available to treat KRAS mutant cancers .
25199829
KRAS is the most frequently mutated oncogene in human cancer , yet no therapies are available to treat CancerKRAS mutant cancers .
25199829
We used two independent reverse genetic approaches to identify components of the RAS signaling pathways required for growth of CancerKRAS mutant tumors .
25199829
Small interfering RNA ( siRNA ) screening of 37 CancerKRAS mutant colorectal cancer cell lines showed that RAF1 suppression was synthetic lethal with MEK inhibition .
25199829
An unbiased kinome short hairpin RNA ( shRNA )-based screen confirmed this synthetic lethal interaction in colorectal as well as in Cancerlung cancer cells bearing KRAS mutations .
25199829
Our data underlie the relevance of developing combinatorial regimens of drugs targeting the RAF-MEK pathway in CancerKRAS mutant tumors .
25210794
HSP90 inhibition represents a promising route to Cancercancer therapy , taking advantage of cancer cell-inherent proteotoxic stress .
25210794
HSP90 inhibition represents a promising route to cancer therapy , taking advantage of Cancercancer cell-inherent proteotoxic stress .
25210794
We tested the efficacy of ganetespib on a series of Cancercolorectal cancer ( CRC )-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis .
25210794
Moreover , CancerCRC tumor samples showed a comparable distribution of UGT1A expression levels .
25210794
The members of the UGT1A gene family are known as drug conjugating liver enzymes involved in drug excretion , but their function in Cancertumor cells is hardly understood .
25210794
UGT1A levels in Cancertumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment .
25212276
To study clonal evolution in Cancerchronic myeloid leukemia ( CML ) , we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome ( Ph )-negative and Ph positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders .
25212276
To study clonal evolution in chronic myeloid leukemia ( CML ) , we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome ( Ph )-negative and Ph positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in Diseasemyeloid disorders .
25216528
As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis , we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low expressing Cancerpancreatic cancer .
25216528
We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and Cancertumor progression .
25216528
Pertuzumab treatment of HER3 expressing Cancerpancreatic cancer cells increased HER3 at the cell membrane , whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it .
25216528
The pertuzumab/9F7-F 11 combination enhanced Cancertumor inhibition and the median survival time in mice xenografted with HER3 expressing pancreatic cancer cells .
25216528
The pertuzumab/9F7-F 11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3 expressing Cancerpancreatic cancer cells .
25216528
Finally , HER2 and HER3 were co-expressed in 11 % and HER3 alone in 27 % of the 45 Cancerpancreatic ductal adenocarcinomas analyzed by immunohistochemistry .
25216528
HER3 is essential for pertuzumab efficacy in HER2low expressing Cancerpancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers .
25216528
HER3 is essential for pertuzumab efficacy in HER2low expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in Cancersuch cancers .
25217772
BACKGROUND : Recently , TERT promoter mutations were identified at high frequencies in Cancercutaneous melanoma tumor samples and cell lines .
25217772
We analyzed a large cohort of Cancermelanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics .
25217772
METHODS : 410 Cancermelanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations .
25217772
RESULTS : TERT promoter mutations were identified in 154 ( 43 % ) of 362 successfully sequenced Cancermelanomas .
25217772
Mutation frequencies varied between Cancermelanoma subtype , being most frequent in melanomas arising in nonacral skin ( 48 % ) and melanomas with occult primary ( 50 % ) , and less frequent in mucosal ( 23 % ) , and acral ( 19 % ) melanomas .
25217772
Mutation frequencies varied between melanoma subtype , being most frequent in Cancermelanomas arising in nonacral skin ( 48 % ) and melanomas with occult primary ( 50 % ) , and less frequent in mucosal ( 23 % ) , and acral ( 19 % ) melanomas .
25217772
Mutation frequencies varied between melanoma subtype , being most frequent in melanomas arising in nonacral skin ( 48 % ) and Cancermelanomas with occult primary ( 50 % ) , and less frequent in mucosal ( 23 % ) , and acral ( 19 % ) melanomas .
25217772
Mutation frequencies varied between melanoma subtype , being most frequent in melanomas arising in nonacral skin ( 48 % ) and melanomas with occult primary ( 50 % ) , and less frequent in mucosal ( 23 % ) , and acral ( 19 % ) Cancermelanomas .
25217772
TERT promoter mutation was independently associated with poorer overall survival in patients with Cancernonacral cutaneous melanomas ( median survival 80 months vs 291 months for wild-type ; hazard ratio corrected for other covariates 2.47 ; 95 % confidence interval [ CI ] = 1.29 to 4.74 ; P = .006 ) .
25217772
CONCLUSIONS : UV induced TERT promoter mutations are one of the most frequent genetic alterations in Cancermelanoma , with frequencies varying depending on melanoma subtype .
25217772
CONCLUSIONS : UV induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma , with frequencies varying depending on Cancermelanoma subtype .
25217772
In Cancernonacral cutaneous melanomas , presence of TERT promoter mutations is independently associated with poor prognosis .
25217772
In nonacral cutaneous melanomas , presence of TERT promoter mutations is independently associated with AdverseOutcomepoor prognosis .
25218906
Both oral agents have antitumour activity in women with Cancerrecurrent ovarian cancer , and their combination was active and had manageable toxicities in a phase 1 trial .
25218906
Both oral agents have antitumour activity in women with recurrent ovarian cancer , and their combination was active and had Diseasemanageable toxicities in a phase 1 trial .
25218906
We investigated whether this combination could improve progression-free survival ( PFS ) compared with olaparib monotherapy in women with Cancerrecurrent platinum sensitive ovarian cancer .
25218906
METHODS : In our randomised , open-label , phase 2 study , we recruited women ( aged > = 18 years ) who had measurable platinum sensitive , relapsed , high-grade serous or endometrioid ovarian , fallopian tube , or Cancerprimary peritoneal cancer , or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres .
25218906
INTERPRETATION : Cediranib plus olaparib seems to improve PFS in women with recurrent platinum sensitive high-grade serous or Cancerendometrioid ovarian cancer , and warrants study in a phase 3 trial .
25219713
( 4 ) CancerMelanoma Unit , Department of Dermatology , Hospital Clinic , IDIBAPS , University of Barcelona , Spain ; Centro Investigacion Biomedica en Enfermedades Raras ( CIBERER ) , Instituto de Salud Carlos III ( ISCIII ) , Barcelona , Spain .
25219713
( 5 ) Institut de Recerca contra la DiseaseLeucemia Josep Carreras , Hospital Germans Trias i Pujol , Universitat Autonoma de Barcelona , Badalona , Spain .
25228534
PURPOSE : The first generation ALK tyrosine kinase inhibitor ( TKI ) crizotinib is a standard therapy for patients with ALK rearranged Cancernon small cell lung cancer ( NSCLC ) .
25228534
EXPERIMENTAL DESIGN : We established a cell line model of alectinib resistance , and analyzed a Cancerresistant tumor specimen from a patient who had relapsed on alectinib .
25232318
BACKGROUND : CancerCarcinoma of unknown primary ( CUP ) accounts for 3-5 % of all adult solid tumors .
25232318
BACKGROUND : Carcinoma of unknown primary ( CUP ) accounts for 3-5 % of all Canceradult solid tumors .
25232318
Molecularly targeted therapy is an emerging approach that may offer greater efficacy and Diseaseless toxicity but is most likely to be effective when pairing a tumor harboring a sensitizing genomic alteration with an agent directed at the altered gene product .
25232318
Molecularly targeted therapy is an emerging approach that may offer greater efficacy and less toxicity but is most likely to be effective when pairing a Cancertumor harboring a sensitizing genomic alteration with an agent directed at the altered gene product .
25232318
The patient was treated with crizotinib , a MET inhibitor , and has experienced a complete normalization of Cancertumor metabolic activity for more than 19 months .
25232318
The use of this approach should be studied prospectively as a strategy for the effective treatment of CUP patients and for avoiding resource-intensive workups to identify the Cancertumor site of origin .
25242168
Antiangiogenic therapy is commonly used for the treatment of Cancercolorectal cancer ( CRC ) .
25242168
MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of Cancertumors .
25242168
In this study , we set out to determine the efficacy of cabozantinib in a preclinical CRC patient derived Cancertumor xenograft model .
25242168
We demonstrate potent inhibitory effects on Cancertumor growth in 80 % of tumors treated .
25242168
We demonstrate potent inhibitory effects on tumor growth in 80 % of Cancertumors treated .
25242168
The greatest antitumor effects were observed in Cancertumors that possess a mutation in the PIK3CA gene .
25264305
BACKGROUND : Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase ( ROS1 ) define a distinct molecular subgroup of Cancernon-small-cell lung cancers ( NSCLCs ) that may be susceptible to therapeutic ROS1 kinase inhibition .
25264305
Crizotinib is a small-molecule tyrosine kinase inhibitor of Canceranaplastic lymphoma kinase ( ALK ) , ROS1 , and another proto-oncogene receptor tyrosine kinase , MET .
25264305
Among 30 Cancertumors that were tested , we identified 7 ROS1 fusion partners : 5 known and 2 novel partner genes .
25265494
BACKGROUND : The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with Cancermelanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone .
25265494
METHODS : We randomly assigned 495 patients with previously untreated unresectable locally advanced or Cancermetastatic BRAF V600 mutation positive melanoma to receive vemurafenib and cobimetinib ( combination group ) or vemurafenib and placebo ( control group ) .
25265494
RESULTS : The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group ( hazard ratio for death or Diseasedisease progression , 0.51 ; 95 % confidence interval [ CI ] , 0.39 to 0.68 ; P < 0.001 ) .
25265494
The number of Cancersecondary cutaneous cancers decreased with the combination therapy .
25265494
CONCLUSIONS : The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600 mutated Cancermetastatic melanoma , at the cost of some increase in toxicity .
25265494
CONCLUSIONS : The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600 mutated metastatic melanoma , at the cost of some increase in Diseasetoxicity .
25267748
PURPOSE : Although p16 protein expression , a surrogate marker of oncogenic human papillomavirus ( HPV ) Diseaseinfection , is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma ( OPSCC ) , its prevalence and significance have not been well established in cancer of the oral cavity , hypopharynx , or larynx , collectively referred as non OPSCC , where HPV infection is less common than in the oropharynx .
25267748
PURPOSE : Although p16 protein expression , a surrogate marker of oncogenic human papillomavirus ( HPV ) infection , is recognized as a prognostic marker in Canceroropharyngeal squamous cell carcinoma ( OPSCC ) , its prevalence and significance have not been well established in cancer of the oral cavity , hypopharynx , or larynx , collectively referred as non OPSCC , where HPV infection is less common than in the oropharynx .
25267748
PURPOSE : Although p16 protein expression , a surrogate marker of oncogenic human papillomavirus ( HPV ) infection , is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma ( OPSCC ) , its prevalence and significance have not been well established in Cancercancer of the oral cavity , hypopharynx , or larynx , collectively referred as non OPSCC , where HPV infection is less common than in the oropharynx .
25267748
PURPOSE : Although p16 protein expression , a surrogate marker of oncogenic human papillomavirus ( HPV ) infection , is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma ( OPSCC ) , its prevalence and significance have not been well established in cancer of the oral cavity , hypopharynx , or larynx , collectively referred as non OPSCC , where DiseaseHPV infection is less common than in the oropharynx .
25268372
BACKGROUND : CancerUterine serous carcinomas ( USCs ) are an aggressive form of uterine cancer that may rely on HER2 and neu amplification as a driver of proliferation .
25268372
BACKGROUND : Uterine serous carcinomas ( USCs ) are an aggressive form of Canceruterine cancer that may rely on HER2 and neu amplification as a driver of proliferation .
25268372
Mice harbouring xenografts of HER2 and neu amplified USC were treated with afatinib by gavage to determine the effect on Cancertumour growth and overall survival .
25268372
Afatinib exposure resulted in abrogation of cell survival , inhibition of HER2 and neu autophosphorylation and S6 transcription factor phosphorylation in HER2 and neu overexpressing USC and inhibited the growth of HER2 amplified Cancertumour xenografts improving overall survival ( P = 0.0017 ) .
25294897
PURPOSE : There is an unmet need for treatment options in Cancerhepatocellular carcinoma ( HCC ) .
25294897
EXPERIMENTAL DESIGN : Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg ( morning )/400 mg ( evening ) , with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade > = 2 hand-foot skin reaction , fatigue , or Diseasegastrointestinal toxicity occurred .
25294897
Primary efficacy endpoint : Diseasedisease control rate .
25294897
Most patients had liver cirrhosis ( 82.9 % ) and Diseasehepatitis B viral infection ( 75.7 % ) .
25294897
DiseaseDisease control rate was 44.8 % ( primary efficacy analysis ; n = 58 ) .
25295501
Everolimus , an inhibitor of the mammalian target of rapamycin ( mTOR ) , is effective in treating Cancertumors harboring alterations in the mTOR pathway .
25295501
Resistance developed in a patient with Cancermetastatic anaplastic thyroid carcinoma after an extraordinary 18-month response .
25295501
Whole-exome sequencing of pretreatment and Cancerdrug resistant tumors revealed a nonsense mutation in TSC2 , a negative regulator of mTOR , suggesting a mechanism for exquisite sensitivity to everolimus .
25295501
The Cancerresistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition .
25300346
Among the patients with Diseaseresponsive disease , time to best response did not differ by PTEN status , but the duration of response was significantly shorter for patients with PTEN loss ( median 4.2 vs. 6.1 months , p = 0.04 ) .
25300346
CONCLUSIONS : PTEN deficiency is an important predictive marker for early resistance to HER2 inhibitor treatment in Cancergastric cancer patients .
25303977
PURPOSE : CancerAggressive cutaneous squamous cell carcinoma ( cSCC ) is often a disfiguring and lethal disease .
25303977
PURPOSE : Aggressive cutaneous squamous cell carcinoma ( cSCC ) is often a disfiguring and Diseaselethal disease .
25303977
RESULTS : Despite the very high-mutational background caused by UV exposure , 23 candidate drivers were identified , including the Cancerwell-known cancer associated genes TP53 , CDKN2A , NOTCH1 , AJUBA , HRAS , CASP8 , FAT1 , and KMT2C ( MLL3 ) .
25303977
Three novel candidate tumor suppressors with putative links to Cancercancer or differentiation , NOTCH2 , PARD3 , and RASA1 , were also identified as possible drivers in cSCC .
25303977
KMT2C mutations were associated with AdverseOutcomepoor outcome and increased bone invasion .
25303977
CONCLUSIONS : The mutational spectrum of cSCC is similar to that of head and Cancerneck squamous cell carcinoma and dominated by tumor-suppressor genes .
25303977
These results improve the foundation for understanding this Diseasedisease and should aid in identifying and treating aggressive cSCC .
25322874
BACKGROUND : More than half of Cancercolorectal tumors harbor activating mutations in RAS and RAF proteins .
25322874
METHODS : Patients with K-RAS mutated Cancercolorectal cancer , progressing on first-line oxaliplatin based chemotherapy with bevacizumab , were eligible for this multicenter open-label phase I/II trial .
25322874
All had K-RAS exon 2 mutated Cancertumors .
25322874
Sixteen patients ( 51.6 % ) had Diseasestable disease for > = 4 weeks , including three > 1 year .
25322874
The most common grade 3 adverse events included diarrhea , Diseaseneutropenia , fatigue , anemia , nausea , and dehydration .
25322874
The most common grade 3 adverse events included diarrhea , neutropenia , fatigue , Diseaseanemia , nausea , and dehydration .
25322874
CONCLUSIONS : Despite termination before full accrual , the point estimates of RR and median PFS show promising results , suggesting that further investigations of MEK inhibition in the treatment of Cancermetastatic colorectal cancer are warranted .
25349473
In 2012 , ponatinib ( Iclusig ( ( R ) ) ) , an orally available pan-BCR-ABL tyrosine kinase inhibitor ( TKI ) developed by ARIAD Pharmaceuticals , Inc. , was approved by the US Food and Drug Administration for use in resistant or Cancerintolerant chronic myeloid leukemia ( CML ) and Philadelphia chromosome positive acute lymphoblastic leukemia ( Ph ( + ) ALL ) .
25349473
In 2012 , ponatinib ( Iclusig ( ( R ) ) ) , an orally available pan-BCR-ABL tyrosine kinase inhibitor ( TKI ) developed by ARIAD Pharmaceuticals , Inc. , was approved by the US Food and Drug Administration for use in resistant or intolerant chronic myeloid leukemia ( CML ) and CancerPhiladelphia chromosome positive acute lymphoblastic leukemia ( Ph ( + ) ALL ) .
25351743
In an ongoing phase I trial , the ALK tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with Cancernon small cell lung cancer ( NSCLC ) harboring ROS1 fusions ; however , cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1 .
25351743
In an ongoing phase I trial , the ALK tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with non small cell lung cancer ( NSCLC ) harboring ROS1 fusions ; however , Cancercancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1 .
25351743
The effect of the identified drug was assessed in the CD74-ROS1-mutant Ba/F3 cells and crizotinib resistant patient derived Cancercancer cells ( MGH047 ) harboring G2032R mutated CD74-ROS1 .
25351745
PURPOSE : Genetic alterations affecting the MAPK and ERK pathway are common in Cancerlung adenocarcinoma ( LAD ) .
25351745
EXPERIMENTAL DESIGN : CancerTumors harboring MEK1 mutations were identified through targeted screening of a large LAD cohort concurrently interrogated for recurrent mutations in MEK1 , EGFR , KRAS , BRAF , ERBB2 and HER2 , NRAS , PIK3CA , and AKT .
25351745
Additional cases were identified through a search of publically Canceravailable cancer genomic datasets .
25351745
CONCLUSIONS : MEK1 mutations define a distinct subset of Cancerlung cancers ( ~ 1 % ) with potential sensitivity to MEK inhibitors .
25370464
PURPOSE : The HER2 mAb , trastuzumab , is a standard therapy for patients with CancerHER2 positive breast cancer before acquired resistance .
25370464
Afatinib , an irreversible , oral , small-molecule ErbB family blocker , shows clinical activity in Cancertrastuzumab-refractory HER2 positive breast cancer .
25370464
Adult women with confirmed advanced and Cancermetastatic HER2 positive breast cancer were eligible .
25370464
Overall , 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg , respectively , experienced dose limiting Diseasetoxicity ( DLT ; all CTCAE grade 3 diarrhea ) .
25370464
Overall , objective response and Diseasedisease control rates were 11 % and 39 % , respectively , with median progression-free survival 111.0 days ( 95 % confidence interval , 56.0-274 .0 ) .
25370464
Signs of clinical activity were seen in Cancertrastuzumab resistant HER2 positive breast cancer , suggesting further investigation with optimal diarrhea management is warranted .
25370471
PURPOSE : This first-in-human dose escalation trial evaluated the safety , tolerability , maximal tolerated dose ( MTD ) , dose limiting Diseasetoxicities ( DLT ) , pharmacokinetics , pharmacodynamics , and preliminary clinical activity of pictilisib ( GDC-0941 ) , an oral , potent , and selective inhibitor of the class I phosphatidylinositol-3-kinases ( PI3K ) .
25370471
PATIENTS AND METHODS : Sixty patients with Cancersolid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily , initially on days 1 to 21 every 28 days and later , using continuous dosing for selected dose levels .
25370471
Pharmacodynamic studies incorporated ( 18 ) F-FDG-PET , and assessment of phosphorylated AKT and S6 ribosomal protein in platelet rich plasma ( PRP ) and Cancertumor tissue .
25370471
The most Diseasecommon toxicities were grade 1-2 nausea , rash , and fatigue , whereas the DLT was grade 3 maculopapular rash ( 450 mg , 2 of 3 patients ; 330 mg , 1 of 7 patients ) .
25370471
Levels of phosphorylated serine 473 AKT were suppressed > 90 % in PRP at 3 hours after dose at the MTD and in Cancertumor at pictilisib doses associated with AUC > 20 h.mumol/L. Significant increase in plasma insulin and glucose levels , and > 25 % decrease in ( 18 ) F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation .
25370471
A patient with CancerV600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria , respectively .
25370471
A patient with V600E BRAF-mutant melanoma and another with Cancerplatinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria , respectively .
25393796
Huntingtin interacting protein 1 ( HIP1 ) has recently been identified as a new fusion partner fused to Canceranaplastic lymphoma kinase ( ALK ) in non-small-cell lung cancer ( NSCLC ) .
25393796
Huntingtin interacting protein 1 ( HIP1 ) has recently been identified as a new fusion partner fused to anaplastic lymphoma kinase ( ALK ) in Cancernon-small-cell lung cancer ( NSCLC ) .
25398829
Inhibitors of PI3Kbeta have potential to reduce growth of Cancertumors in which loss of PTEN drives tumor progression .
25398829
Inhibitors of PI3Kbeta have potential to reduce growth of tumors in which loss of CancerPTEN drives tumor progression .
25398829
We have then explored the antitumor effects as single agent and in combination with docetaxel in triple negative breast ( TNBC ) and Cancerprostate cancer models .
25398829
In vivo , AZD8186 inhibits PI3K pathway biomarkers in prostate and CancerTNBC tumors .
25398829
Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure , and that increased Cancertumor control is achieved when AZD8186 is used in combination with docetaxel .
25398829
AZD8186 is a potent inhibitor of PI3Kbeta with activity against PI3Kdelta signaling , and has potential to reduce growth of Cancertumors dependent on dysregulated PTEN for growth .
25398829
Moreover , AZD8186 can be combined with docetaxel , a chemotherapy commonly used to treat advanced TBNC and Cancerprostate tumors .
25399551
BACKGROUND : The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously Canceruntreated metastatic melanoma with BRAF V600E or V600K mutations .
25399551
METHODS : In this open-label , phase 3 trial , we randomly assigned 704 patients with Cancermetastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib ( 150 mg twice daily ) and trametinib ( 2 mg once daily ) or vemurafenib ( 960 mg twice daily ) orally as first-line therapy .
25399551
CancerCutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1 % of patients in the combination-therapy group and 18 % of those in the vemurafenib group .
25399551
Cutaneous squamous-cell carcinoma and Cancerkeratoacanthoma occurred in 1 % of patients in the combination-therapy group and 18 % of those in the vemurafenib group .
25399551
CONCLUSIONS : Dabrafenib plus trametinib , as compared with vemurafenib monotherapy , significantly improved overall survival in previously untreated patients with Cancermetastatic melanoma with BRAF V600E or V600K mutations , without increased overall toxicity .
25399551
CONCLUSIONS : Dabrafenib plus trametinib , as compared with vemurafenib monotherapy , significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations , without increased Diseaseoverall toxicity .
25408655
Suspected metastatic site lesions that are poorly differentiated present a diagnostic challenge when morphologic and immunohistochemical profiling can not establish the Cancerprimary tumor site .
25409150
Broad and Cancerdeep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones .
25409150
Broad and deep tumour genome sequencing has shed new light on Cancertumour heterogeneity and provided important insights into the evolution of metastases arising from different clones .
25409150
There is an additional layer of complexity , in that Cancertumour evolution may be influenced by selective pressure provided by therapy , in a similar fashion to that occurring in infectious diseases .
25409150
There is an additional layer of complexity , in that tumour evolution may be influenced by selective pressure provided by therapy , in a similar fashion to that occurring in Diseaseinfectious diseases .
25409150
Here we studied Cancertumour genomic evolution in a patient ( index patient ) with metastatic breast cancer bearing an activating PIK3CA ( phosphatidylinositol-4 ,5-bisphosphate 3-kinase , catalytic subunit alpha , PI ( 3 ) Kalpha ) mutation .
25409150
Here we studied tumour genomic evolution in a patient ( index patient ) with Cancermetastatic breast cancer bearing an activating PIK3CA ( phosphatidylinositol-4 ,5-bisphosphate 3-kinase , catalytic subunit alpha , PI ( 3 ) Kalpha ) mutation .
25409150
All metastatic lesions , when compared to the Cancerpre-treatment tumour , had a copy loss of PTEN ( phosphatase and tensin homolog ) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations , resulting in the loss of PTEN expression .
25409150
Acquired bi-allelic loss of PTEN was found in one of these patients , whereas in two others PIK3CA mutations present in the Cancerprimary tumour were no longer detected at the time of progression .
25412851
We assessed the frequency and clinicopathologic significance of 19 genes currently identified as significantly mutated in myeloid neoplasms , RUNX1 , ASXL1 , TET2 , CEBPA , IDH1 , IDH2 , DNMT3A , FLT3 , NPM1 , TP53 , NRAS , EZH2 , CBL , U2AF1 , SF3B1 , SRSF2 , JAK2 , CSF3R , and SETBP1 , across 93 cases of Canceracute myeloid leukemia ( AML ) using capture target enrichment and next generation sequencing .
25423555
OBJECTIVES : Recently , aberrations in the gene encoding for ataxia-telangiectasia-mutated ( ATM ) protein kinase have been reported for Cancerpancreatic ductal adenocarcinomas ( PDAC ) .
25424858
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in Cancerseveral tumour types including myelodysplastic syndromes , chronic lymphocytic leukaemia , uveal melanoma , and pancreatic cancer , and at lower frequencies in breast cancer .
25424858
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including Diseasemyelodysplastic syndromes , chronic lymphocytic leukaemia , uveal melanoma , and pancreatic cancer , and at lower frequencies in breast cancer .
25424858
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes , Diseasechronic lymphocytic leukaemia , uveal melanoma , and pancreatic cancer , and at lower frequencies in breast cancer .
25424858
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes , chronic lymphocytic leukaemia , Canceruveal melanoma , and pancreatic cancer , and at lower frequencies in breast cancer .
25424858
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes , chronic lymphocytic leukaemia , uveal melanoma , and Cancerpancreatic cancer , and at lower frequencies in breast cancer .
25424858
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes , chronic lymphocytic leukaemia , uveal melanoma , and pancreatic cancer , and at lower frequencies in Cancerbreast cancer .
25424858
To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of Cancerbreast cancer , we performed a re-analysis of published exome and whole genome sequencing data .
25424858
This analysis revealed that mutations in spliceosomal component genes occurred in 5.6 % of Cancerunselected breast cancers , including hotspot mutations in the SF3B1 gene , which were found in 1.8 % of unselected breast cancers .
25424858
This analysis revealed that mutations in spliceosomal component genes occurred in 5.6 % of unselected breast cancers , including hotspot mutations in the SF3B1 gene , which were found in 1.8 % of Cancerunselected breast cancers .
25424858
SF3B1 mutations were significantly associated with DiseaseER positive disease , AKT1 mutations , and distinct copy number alterations .
25424858
Additional profiling of hotspot mutations in a panel of special histological subtypes of Cancerbreast cancer showed that 16 % and 6 % of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation .
25424858
Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16 % and 6 % of papillary and Cancermucinous carcinomas of the breast harboured the SF3B1 K700E mutation .
25424858
RNA sequencing identified differentially spliced events expressed in Cancertumours with SF3B1 mutations including the protein coding genes TMEM14C , RPL31 , DYNL11 , UQCC , and ABCC5 , and the long non coding RNA CRNDE .
25424858
Albeit rare , SF3B1 mutations result in alternative splicing events , and may constitute drivers and a novel therapeutic target in a subset of Cancerbreast cancers .
25433983
INTRODUCTION : Current targeted therapy proves no effective outcomes in Cancerlung squamous cell carcinoma ( SQCC ) .
25433983
FGFR1 amplification was significantly correlated with Cancerlymph node metastasis ( OR : 2.27 ; 95 % CI : 1.62-3 .20 ; p = 0.000 ) , but not correlated with gender ( OR : 1.12 ; 95 % CI : 0.90-1 .38 ; p = 0.91 ) , differentiation ( OR : 1.02 ; 95 % CI : 0.76-1 .38 ; p = 0.959 ) and stage ( OR : 0.93 ; 95 % CI : 0.73-1 .19 ; p = 0.877 ) in lung SQCC patients .
25433983
FGFR1 amplification trends to correlate with Cancerlymph node metastasis and smoking .
25445424
Author information : ( 1 ) Department of Surgery , University of DiseaseCalifornia , San Diego , School of Medicine , La Jolla , CA .
25445424
( 2 ) Department of Medicine , University of DiseaseCalifornia , San Diego , School of Medicine , La Jolla , CA ; Moores Cancer Center , University of California , San Diego , La Jolla , CA .
25445424
( 2 ) Department of Medicine , University of California , San Diego , School of Medicine , La Jolla , CA ; Moores Cancer Center , University of DiseaseCalifornia , San Diego , La Jolla , CA .
25445424
( 3 ) Department of Surgery , University of DiseaseCalifornia , San Diego , School of Medicine , La Jolla , CA ; Moores Cancer Center , University of California , San Diego , La Jolla , CA .
25445424
( 3 ) Department of Surgery , University of California , San Diego , School of Medicine , La Jolla , CA ; Moores Cancer Center , University of DiseaseCalifornia , San Diego , La Jolla , CA .
25445424
( 4 ) Moores Cancer Center , University of DiseaseCalifornia , San Diego , La Jolla , CA ; Department of Family and Preventive Medicine , University of California , San Diego , School of Medcine , La Jolla , CA .
25445424
( 4 ) Moores Cancer Center , University of California , San Diego , La Jolla , CA ; Department of Family and Preventive Medicine , University of DiseaseCalifornia , San Diego , School of Medcine , La Jolla , CA .
25470694
BACKGROUND : The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for Canceradvanced ALK positive non-small-cell lung cancer ( NSCLC ) is unknown .
25470694
METHODS : We conducted an open-label , phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK positive nonsquamous NSCLC who had received no previous systemic treatment for Diseaseadvanced disease .
25470694
Crossover to crizotinib treatment after Diseasedisease progression was permitted for patients receiving chemotherapy .
25470694
The most common adverse events with crizotinib were Diseasevision disorders , diarrhea , nausea , and edema , and the most common events with chemotherapy were nausea , fatigue , vomiting , and decreased appetite .
25470694
As compared with chemotherapy , crizotinib was associated with greater reduction in Cancerlung cancer symptoms and greater improvement in quality of life .
25502557
BACKGROUND : CancerNeuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients .
25502557
BACKGROUND : Neuroblastoma is a Cancerpediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients .
25502557
BACKGROUND : Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to Diseasefatal disease in high-risk patients .
25502557
The identification of single nucleotide polymorphisms ( SNPs ) may help explain the heterogeneity of Cancerneuroblastoma and assist in identifying patients at higher risk for poor survival .
25502557
The identification of single nucleotide polymorphisms ( SNPs ) may help explain the heterogeneity of neuroblastoma and assist in identifying patients at higher AdverseOutcomerisk for poor survival .
25502557
SNPs in the TP53 pathway are of special importance , as several studies have reported associations between TP53 pathway SNPs and Cancercancer .
25502557
Of note , less than 2 % of Cancerneuroblastoma tumors have a TP53 mutation at diagnosis .
25502557
PATIENTS AND METHODS : We selected 21 of the most frequently studied SNPs in the TP53 pathway and evaluated their association with outcome in 500 Cancerneuroblastoma patients using TaqMan allelic discrimination assays .
25502557
RESULTS AND CONCLUSION : We investigated the impact of 21 SNPs on overall survival , event-free survival , age at diagnosis , MYCN status , and stage of the Diseasedisease in 500 neuroblastoma patients .
25502557
RESULTS AND CONCLUSION : We investigated the impact of 21 SNPs on overall survival , event-free survival , age at diagnosis , MYCN status , and stage of the disease in 500 Cancerneuroblastoma patients .
25502557
A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN amplified Cancerneuroblastoma tumors .
25504439
Attempts to directly block the Cancermutant neuroblastoma rat sarcoma oncogene ( NRAS ) protein , a driving mutation in many cancer types , have been unsuccessful .
25504439
Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene ( NRAS ) protein , a driving mutation in Cancermany cancer types , have been unsuccessful .
25504439
Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines , including Cancermelanoma cells , melanoma cells with acquired trametinib resistance , lung cancer and neuroblastoma cells .
25504439
Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines , including melanoma cells , Cancermelanoma cells with acquired trametinib resistance , lung cancer and neuroblastoma cells .
25504439
Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines , including melanoma cells , melanoma cells with acquired trametinib resistance , Cancerlung cancer and neuroblastoma cells .
25504439
Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines , including melanoma cells , melanoma cells with acquired trametinib resistance , lung cancer and Cancerneuroblastoma cells .
25504439
This dual therapy synergistically reduced cell viability in vitro and Cancerxenograft tumor growth in vivo .
25504439
We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of CancerNRAS mutant cancers .
25515853
Resistance to treatment is the main problem of targeted treatment for Cancercancer .
25515853
This is the first observation of a secondary BRAF mutation in a vemurafenib resistant patient derived Cancermelanoma sample , which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance .
25515853
Moreover , this study hints toward an important role for Cancertumor heterogeneity in determining the outcome of targeted treatments .
25517749
Genetic studies have established Canceranaplastic lymphoma kinase ( ALK ) , a cell surface receptor tyrosine kinase , as a tractable molecular target in neuroblastoma .
25517749
Genetic studies have established anaplastic lymphoma kinase ( ALK ) , a cell surface receptor tyrosine kinase , as a tractable molecular target in Cancerneuroblastoma .
25517749
We describe comprehensive genomic , biochemical , and computational analyses of ALK mutations across 1,596 Cancerdiagnostic neuroblastoma samples .
25517749
ALK tyrosine kinase domain mutations occurred in 8 % of samples -- at three hot spots and 13 minor sites -- and correlated significantly with poorer survival in high- and Cancerintermediate-risk neuroblastoma .
25517749
Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in Cancerneuroblastoma and will allow tailoring of ALK targeted therapy to specific mutations .
25520391
PURPOSE : Formalin fixed , Cancerparaffin embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis related genes to identify prognostic or predictive biomarkers for cetuximab treatment .
25520391
PATIENTS AND METHODS : Patients ( 238 total ) with Cancerfirst-line metastatic colorectal cancer ( mCRC ) were randomized to FOLFOX or FOLFIRI chemotherapy +/- cetuximab .
25520391
RESULTS : CancerHigh tumor mRNA levels of HER2 [ hazard ratio ( HR ) , 0.64 ; P = 0.002 ] and EREG ( HR , 0.89 ; P = 0.016 ) were prognostic markers associated with longer PFS across all patients .
25520391
In KRAS wild-type ( WT ) Cancertumors , low HER3 expression was associated with longer OS from cetuximab treatment , whereas high HER3 expression was associated with shorter OS from cetuximab treatment ( chemo + cetuximab : HR , 1.15 ; chemo-only : HR , 0.48 ; Pinteraction = 0.029 ) .
25520391
High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT ( chemo + cetuximab : HR , 0.91 ; chemo-only : HR , 1.57 ; Pinteraction = 0.026 ) and KRAS-mutant ( Mut ) Cancertumors ( chemo + cetuximab : HR , 0.80 ; chemo-only : HR , 1.29 ; P = 0.025 ) .
25524798
BACKGROUND : Palbociclib ( PD-0332991 ) is an oral , small-molecule inhibitor of cyclin dependent kinases ( CDKs ) 4 and 6 with preclinical evidence of growth-inhibitory activity in Canceroestrogen receptor positive breast cancer cells and synergy with anti-oestrogens .
25524798
We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced , oestrogen receptor positive , CancerHER2 negative breast cancer .
25524798
METHODS : In this open-label , randomised phase 2 study , postmenopausal women with advanced oestrogen receptor positive and CancerHER2 negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate .
25524798
METHODS : In this open-label , randomised phase 2 study , postmenopausal women with advanced oestrogen receptor positive and HER2 negative breast cancer who had not received any systemic treatment for their Diseaseadvanced disease were eligible to participate .
25524798
Patients were enrolled in two separate cohorts that accrued sequentially : in cohort 1 , patients were enrolled on the basis of their oestrogen receptor positive and HER2 negative biomarker status alone , whereas in cohort 2 they were also required to have Cancercancers with amplification of cyclin D1 ( CCND1 ) , loss of p16 ( INK4A or CDKN2A ) , or both .
25524798
In both cohorts , patients were randomly assigned 1:1 via an interactive web based randomisation system , stratified by Diseasedisease site and disease-free interval , to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg , given once daily for 3 weeks followed by 1 week off over 28-day cycles .
25524798
Grade 3-4 Diseaseneutropenia was reported in 45 ( 54 % ) of 83 patients in the palbociclib plus letrozole group versus one ( 1 % ) of 77 patients in the letrozole group , leucopenia in 16 ( 19 % ) versus none , and fatigue in four ( 4 % ) versus one ( 1 % ) .
25524798
Grade 3-4 neutropenia was reported in 45 ( 54 % ) of 83 patients in the palbociclib plus letrozole group versus one ( 1 % ) of 77 patients in the letrozole group , Diseaseleucopenia in 16 ( 19 % ) versus none , and fatigue in four ( 4 % ) versus one ( 1 % ) .
25524798
No cases of Diseasefebrile neutropenia or neutropenia related infections were reported during the study .
25524798
No cases of febrile neutropenia or Diseaseneutropenia related infections were reported during the study .
25524798
INTERPRETATION : The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor positive and CancerHER2 negative breast cancer .
25537159
PATIENTS AND METHODS : Treatment-naive , HER2 positive BC patients with stage IIIA , B , C or Diseaseinflammatory disease were randomized 1:1:1 to daily afatinib ( 50 mg ) , lapatinib ( 1500 mg ) , or weekly trastuzumab ( 4 mg/kg loading dose , then 2 mg/kg/wk ) for 6 weeks until surgery or follow-up neoadjuvant treatment .
25537159
The primary end point was objective response rate according to Response Evaluation Criteria in CancerSolid Tumors ( version 1.0 ) .
25537159
Eleven patients had Diseasestable disease ( best response ) ; 1 lapatinib- and 1 trastuzumab treated patient had progressive disease .
25537159
Eleven patients had stable disease ( best response ) ; 1 lapatinib- and 1 trastuzumab treated patient had Diseaseprogressive disease .
25537159
All 10 afatinib treated patients experienced drug related adverse events ( commonly diarrhea , Diseasedermatitis acneiform , and paronychia ) versus 6 of 8 lapatinib- ( diarrhea and rash ) and 5 of 11 trastuzumab treated patients ( vomiting and arthralgia ) .
25542057
BACKGROUND : We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel , with a view to exploring the combination 's activity in Cancermelanoma lacking a BRAF V600 mutation .
25542057
Eligible patients had advanced Cancermelanoma and could have received up to two previous lines of treatment for metastatic disease .
25542057
Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for Diseasemetastatic disease .
25542057
FINDINGS : 15 patients were enrolled , all but one of whose Cancermelanoma was wild type for BRAF at codon 600 .
25542057
In this small group promising progression free and overall survival were observed in patients with Cancermelanoma lacking a V600 BRAF mutation .
25542901
PURPOSE : ERBB3 is overexpressed in a broad spectrum of Cancerhuman cancers , and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents .
25542901
PURPOSE : ERBB3 is overexpressed in a broad spectrum of human cancers , and its aberrant activation is associated with Cancertumor pathogenesis and therapeutic resistance to various anticancer agents .
25542901
AV-203 is a humanized IgG1 and kappa ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with Canceradvanced solid tumors .
25542901
EXPERIMENTAL DESIGN : We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of Cancerhuman cancers .
25542901
To identify biomarkers that can predict response to AV-203 , the relationship between Cancertumor growth inhibition ( TGI ) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models .
25542901
To identify biomarkers that can predict response to AV-203 , the relationship between tumor growth inhibition ( TGI ) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these Cancertumor models .
25542901
The correlation between the levels of NRG1 expression in Cancertumors and their response to ERBB3 inhibition by AV-203 was further validated using patient derived tumor explant models .
25542901
The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient derived Cancertumor explant models .
25542901
CONCLUSIONS : NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in Cancerpreclinical human cancer models .
25544636
In PTEN mutated Cancertumors , we show that PI3Kalpha activity is suppressed and PI3K signaling is driven by PI3Kbeta .
25544636
A selective inhibitor of PI3Kbeta inhibits the Akt and mTOR pathway in these Cancertumors but not in those driven by receptor tyrosine kinases .
25544636
This rebound is suppressed and Cancertumor growth inhibition enhanced with combined inhibition of PI3Kalpha and PI3Kbeta .
25544636
In PTEN deficient models of Cancerprostate cancer , this effective inhibition of PI3K causes marked activation of androgen receptor activity .
25544636
Combined inhibition of both PI3K isoforms and androgen receptor results in Cancermajor tumor regressions .
25544710
ETS gene fusions involving ERG , ETV1 , ETV4 , ETV5 , and FLI1 define a distinct class of Cancerprostate cancer ( PCa ) , and this might have a bearing on diagnosis , prognosis , and rational therapeutic targeting .
25544710
In the current study , we focused on the clinicopathological significance of ETV4 in Chinese PCa patients and the mechanisms whereby ETV4 overexpression mediates Cancertumor invasion in the prostate .
25544710
Clinically , ETV4 overexpression was significantly correlated with Gleason score ( P = 0.045 ) and Cancerpathological tumor stage ( P = 0.041 ) .
25550549
BACKGROUND and AIM : The purpose of the present study was to explore the antiproliferative effect of BYL719 , a specific inhibitor for phosphatidylinositol 3-kinase ( PI3K ) p110alpha , in human head and Cancerneck cancer cell lines , as a single agent or in combination with the irreversible EGFR tyrosine kinase inhibitor , dacomitinib .
25550549
MATERIALS AND METHODS : Six head and Cancerneck cancer cell lines consisting of two PIK3CA mutant cell lines , SNU-1076 and Detroit562 , and four PIK3CA wild-type cell lines , SNU-1066 , SNU-1041 , FaDu and SCC25 , were analyzed .
25550549
CONCLUSION : BYL719 , a PI3K alpha selective blocker , could be a promising factor in the treatment of head and Cancerneck cancer either as a single agent or in combination with dacomitinib .
25557953
BACKGROUND & AIMS : CancerFibrolamellar hepatocellular carcinoma ( FLC ) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis .
25557953
BACKGROUND & AIMS : Fibrolamellar hepatocellular carcinoma ( FLC ) is a Cancerrare primary hepatic cancer that develops in children and young adults without cirrhosis .
25557953
METHODS : By using 78 clinically annotated FLC samples , we performed whole-transcriptome ( n = 58 ) , single-nucleotide polymorphism array ( n = 41 ) , and next generation sequencing ( n = 48 ) analyses ; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this Cancercancer ( n = 73 ) .
25557953
The genomic identification of significant targets in a Cancercancer algorithm was used to identify chromosomal aberrations , MuTect and VarScan2 were used to identify somatic mutations , and the random survival forest was used to determine patient prognoses .
25557953
RESULTS : Unsupervised gene expression clustering showed 3 robust molecular classes of Cancertumors : the proliferation class ( 51 % of samples ) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation ; the inflammation class ( 26 % of samples ) had altered expression of genes that regulate inflammation and cytokine enriched production ; and the unannotated class ( 23 % of samples ) had a gene expression signature that was not associated previously with liver tumors .
25557953
RESULTS : Unsupervised gene expression clustering showed 3 robust molecular classes of tumors : the proliferation class ( 51 % of samples ) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation ; the Diseaseinflammation class ( 26 % of samples ) had altered expression of genes that regulate inflammation and cytokine enriched production ; and the unannotated class ( 23 % of samples ) had a gene expression signature that was not associated previously with liver tumors .
25557953
RESULTS : Unsupervised gene expression clustering showed 3 robust molecular classes of tumors : the proliferation class ( 51 % of samples ) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation ; the inflammation class ( 26 % of samples ) had altered expression of genes that regulate Diseaseinflammation and cytokine enriched production ; and the unannotated class ( 23 % of samples ) had a gene expression signature that was not associated previously with liver tumors .
25557953
RESULTS : Unsupervised gene expression clustering showed 3 robust molecular classes of tumors : the proliferation class ( 51 % of samples ) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation ; the inflammation class ( 26 % of samples ) had altered expression of genes that regulate inflammation and cytokine enriched production ; and the unannotated class ( 23 % of samples ) had a gene expression signature that was not associated previously with Cancerliver tumors .
25557953
FLC samples also contained mutations in Cancercancer related genes such as BRCA2 ( in 4.2 % of samples ) , which are uncommon in liver neoplasms .
25557953
However , FLCs did not contain mutations most commonly detected in Cancerliver cancers .
25557953
FLCs contain mutations and chromosomal aberrations not previously associated with Cancerliver cancer , and almost 80 % contain the DNAJB1-PRKACA fusion transcript .
25567352
Neurofibromatosis type 2 ( NF2 ) is a Diseasegenetic disorder with bilateral vestibular schwannomas ( VS ) as the most frequent manifestation .
25567352
Neurofibromatosis type 2 ( NF2 ) is a genetic disorder with Cancerbilateral vestibular schwannomas ( VS ) as the most frequent manifestation .
25567352
Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of CancerNF2-schwannomas .
25567352
Everolimus was administered orally for 12 months and , if the decrease in Cancertumor volume was > 20 % from baseline , treatment was continued for 12 additional months .
25567352
Four patients had Diseaseprogressive disease , and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment .
25567352
Four patients had progressive disease , and five patients had Diseasestable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment .
25567352
In these patients , Cancertumor growth resumed within 3-6 months after treatment discontinuation .
25567352
Time to Cancertumor progression increased threefold from 4.2 months before treatment to > 12 months .
25586468
BACKGROUND : The epidermal growth factor receptor variant III deletion mutation , EGFRvIII , is expressed in ~ 30 % of Cancerprimary glioblastoma and linked to poor long-term survival .
25586468
METHODS : Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII expressing ( EGFRvIII+ ) Cancerglioblastoma after gross total resection and chemoradiation .
25586468
EGFRvIII was eliminated in 4/6 ( 67 % ) Cancertumor samples obtained after > 3 months of therapy .
25587029
As a cell cycle inhibitor and tumor suppressor , p27 is frequently misregulated in Cancerhuman cancers .
25587029
Increased degradation is the most common mechanism of misregulation , however in some Cancercancers , p27 is mislocalized from its cell cycle inhibitory location in the nucleus , to the cytoplasm .
25587029
Therefore , an important question is whether localization of p27 to the cytoplasm in Cancertumor cells is primarily a mechanism for cancelling its inhibitory effect on cell proliferation , or whether cytoplasmic p27 has more direct oncogenic actions .
25587029
To study p27 mislocalization in Cancerhuman cancers we screened a panel of common breast cancer cell lines .
25587029
To study p27 mislocalization in human cancers we screened a panel of Cancercommon breast cancer cell lines .
25587029
To address the significance of p27 mislocalization in CancerHer2+ breast cancer cells we interrogated the cellular response to the dual-Her2 and EGFR kinase inhibitor , lapatinib .
25587029
Moreover , expression of a constitutively cytoplasmic form of p27 ( p27DeltaNLS ) reversed the lapatinib induced apoptosis , suggesting that cytoplasmic p27 contributed to lapatinib resistance in CancerHer2+ breast cancer cells by suppressing apoptosis .
25587029
Our results suggest that p27 localization may be useful as a predictive biomarker of therapeutic response in patients with CancerHer2+ breast cancers .
25589191
BACKGROUND : We aimed to assess the effect of afatinib on overall survival of patients with CancerEGFR mutation positive lung adenocarcinoma through an analysis of data from two open-label , randomised , phase 3 trials .
25589191
METHODS : Previously untreated patients with EGFR mutation positive stage IIIB or IV Cancerlung adenocarcinoma were enrolled in LUX-Lung 3 ( n = 345 ) and LUX-Lung 6 ( n = 364 ) .
25589191
However , in preplanned analyses , overall survival was significantly longer for patients with Cancerdel19 positive tumours in the afatinib group than in the chemotherapy group in both trials : in LUX-Lung 3 , median overall survival was 33.3 months ( 95 % CI 26.8-41 .5 ) in the afatinib group versus 21.1 months ( 16.3-30 .7 ) in the chemotherapy group ( HR 0.54 , 95 % CI 0.36-0 .79 , p = 0.0015 ) ; in LUX-Lung 6 , it was 31.4 months ( 95 % CI 24.2-35 .3 ) versus 18.4 months ( 14.6-25 .6 ) , respectively ( HR 0.64 , 95 % CI 0.44-0 .94 , p = 0.023 ) .
25589191
By contrast , there were no significant differences by treatment group for patients with CancerEGFR Leu858Arg positive tumours in either trial : in LUX-Lung 3 , median overall survival was 27.6 months ( 19.8-41 .7 ) in the afatinib group versus 40.3 months ( 24.3-not estimable ) in the chemotherapy group ( HR 1.30 , 95 % CI 0.80-2 .11 , p = 0.29 ) ; in LUX-Lung 6 , it was 19.6 months ( 95 % CI 17.0-22 .1 ) versus 24.3 months ( 19.0-27 .0 ) , respectively ( HR 1.22 , 95 % CI 0.81-1 .83 , p = 0.34 ) .
25589191
In both trials , the most common afatinib related grade 3-4 adverse events were rash or acne ( 37 [ 16 % ] of 229 patients in LUX-Lung 3 and 35 [ 15 % ] of 239 patients in LUX-Lung 6 ) , diarrhoea ( 33 [ 14 % ] and 13 [ 5 % ] ) , paronychia ( 26 [ 11 % ] in LUX-Lung 3 only ) , and Diseasestomatitis or mucositis ( 13 [ 5 % ] in LUX-Lung 6 only ) .
25589191
In both trials , the most common afatinib related grade 3-4 adverse events were rash or acne ( 37 [ 16 % ] of 229 patients in LUX-Lung 3 and 35 [ 15 % ] of 239 patients in LUX-Lung 6 ) , diarrhoea ( 33 [ 14 % ] and 13 [ 5 % ] ) , paronychia ( 26 [ 11 % ] in LUX-Lung 3 only ) , and stomatitis or Diseasemucositis ( 13 [ 5 % ] in LUX-Lung 6 only ) .
25589191
In LUX-Lung 3 , Diseaseneutropenia ( 20 [ 18 % ] of 111 patients ) , fatigue ( 14 [ 13 % ] ) and leucopenia ( nine [ 8 % ] ) were the most common chemotherapy related grade 3-4 adverse events , while in LUX-Lung 6 , the most common chemotherapy related grade 3-4 adverse events were neutropenia ( 30 [ 27 % ] of 113 patients ) , vomiting ( 22 [ 19 % ] ) , and leucopenia ( 17 [ 15 % ] ) .
25589191
In LUX-Lung 3 , neutropenia ( 20 [ 18 % ] of 111 patients ) , fatigue ( 14 [ 13 % ] ) and Diseaseleucopenia ( nine [ 8 % ] ) were the most common chemotherapy related grade 3-4 adverse events , while in LUX-Lung 6 , the most common chemotherapy related grade 3-4 adverse events were neutropenia ( 30 [ 27 % ] of 113 patients ) , vomiting ( 22 [ 19 % ] ) , and leucopenia ( 17 [ 15 % ] ) .
25589191
In LUX-Lung 3 , neutropenia ( 20 [ 18 % ] of 111 patients ) , fatigue ( 14 [ 13 % ] ) and leucopenia ( nine [ 8 % ] ) were the most common chemotherapy related grade 3-4 adverse events , while in LUX-Lung 6 , the most common chemotherapy related grade 3-4 adverse events were Diseaseneutropenia ( 30 [ 27 % ] of 113 patients ) , vomiting ( 22 [ 19 % ] ) , and leucopenia ( 17 [ 15 % ] ) .
25589191
In LUX-Lung 3 , neutropenia ( 20 [ 18 % ] of 111 patients ) , fatigue ( 14 [ 13 % ] ) and leucopenia ( nine [ 8 % ] ) were the most common chemotherapy related grade 3-4 adverse events , while in LUX-Lung 6 , the most common chemotherapy related grade 3-4 adverse events were neutropenia ( 30 [ 27 % ] of 113 patients ) , vomiting ( 22 [ 19 % ] ) , and Diseaseleucopenia ( 17 [ 15 % ] ) .
25589191
The absence of an effect in patients with Leu858Arg EGFR mutations suggests that DiseaseEGFR del19 positive disease might be distinct from Leu858Arg positive disease and that these subgroups should be analysed separately in future trials .
25589191
The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19 positive disease might be distinct from DiseaseLeu858Arg positive disease and that these subgroups should be analysed separately in future trials .
25589621
PURPOSE : CancerBRAF-mutant metastatic colorectal cancer ( mCRC ) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors .
25589621
PURPOSE : BRAF-mutant metastatic colorectal cancer ( mCRC ) forms an aggressive subset of Cancercolorectal cancer with minimal response to selective RAF inhibitors .
25589621
Preclinical data show that reactivation of EGFR signaling occurs in Cancercolorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity .
25589621
Treatment was well tolerated , with Diseaseless cutaneous toxicity than would be expected with either agent , and no cases of keratoacanthomas and squamous cell carcinomas .
25589621
Treatment was well tolerated , with less cutaneous toxicity than would be expected with either agent , and no cases of Cancerkeratoacanthomas and squamous cell carcinomas .
25589621
Treatment was well tolerated , with less cutaneous toxicity than would be expected with either agent , and no cases of keratoacanthomas and Cancersquamous cell carcinomas .
25589621
CancerTumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients ( 100 % and 64 % regression lasting 40 and 24 weeks , respectively ) , and stable disease lasting over 6 months in 2 patients .
25589621
Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients ( 100 % and 64 % regression lasting 40 and 24 weeks , respectively ) , and Diseasestable disease lasting over 6 months in 2 patients .
25589621
CONCLUSIONS : Combined RAF and EGFR inhibition is well tolerated , with Diseaseless cutaneous toxicity than would be expected with either agent , and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC .
25590338
Approximately 25 % of Cancerbreast cancers overexpress and depend on the receptor tyrosine kinase ERBB2 , one of 4 ERBB family members .
25590338
Moreover , ERBB4 was upregulated at the protein level in CancerERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment .
25590338
Our results suggest that although ERBB4 is dispensable for Cancernaive ERBB2+ breast cancer cells , it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors , lapatinib and trastuzumab .
25590338
Our results suggest that although ERBB4 is dispensable for naive ERBB2+ breast cancer cells , it may play a key role in the survival of CancerERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors , lapatinib and trastuzumab .
25601188
CancerSmall-cell lung cancer ( SCLC ) easily recurs with multidrug resistance phenotype .
25601188
Human epidermal growth factor receptor 2 ( HER2 ) expression correlates with AdverseOutcomepoor prognosis in extensive disease-SCLC .
25601188
One patient achieved partial response after the first cycle and received 6 cycles in total without Diseasedisease progression for 4.5 months .
25601188
The other also received 4 cycles and kept Diseasestable disease for 3.5 months .
25625803
CONTEXT AND OBJECTIVE : CancerOncocytic thyroid carcinoma , also known as Hurthle cell thyroid carcinoma , accounts for only a small percentage of all thyroid cancers .
25625803
CONTEXT AND OBJECTIVE : Oncocytic thyroid carcinoma , also known as CancerHurthle cell thyroid carcinoma , accounts for only a small percentage of all thyroid cancers .
25625803
CONTEXT AND OBJECTIVE : Oncocytic thyroid carcinoma , also known as Hurthle cell thyroid carcinoma , accounts for only a small percentage of all Cancerthyroid cancers .
25625803
However , this Cancermalignancy often presents at an advanced stage and poses unique challenges to patients and clinicians .
25625803
Surgical resection of the Cancertumor accompanied in some cases by radioactive iodine treatment , radiation , and chemotherapy are the established modes of therapy .
25625803
Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of Diseasedisease and thus opportunities for more effective clinical management .
25625803
DESIGN AND PATIENTS : Initially , two Canceroncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing .
25625803
Subsequently , 72 Canceroncocytic thyroid carcinomas , one cell line , and five Hurthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I ( MEN1 ) gene .
25625803
Subsequently , 72 oncocytic thyroid carcinomas , one cell line , and five CancerHurthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I ( MEN1 ) gene .
25625803
RESULTS : Here we report the identification of MEN1 loss-of-function mutations in 4 % of patients diagnosed with Canceroncocytic thyroid carcinoma .
25625803
Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these Cancertumors .
25625803
CONCLUSION : Menin , a ubiquitously expressed nuclear protein , is a well characterized tumor suppressor whose loss is the cause of DiseaseMEN1 syndrome .
25625803
Mutations of this gene in a subset of CancerHurthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis .
25636205
A pathologic complete response to neoadjuvant chemotherapy ( NAC ) containing platinum is a strong prognostic determinant for patients with Cancermuscle-invasive bladder cancer ( MIBC ) .
25636205
Despite comprehensive molecular characterization of Cancerbladder cancer , associations of molecular alterations with treatment response are still largely unknown .
25636205
DNA was isolated from Cancerprechemotherapy tumor tissue and used for next generation sequencing of 178 cancer associated genes ( discovery cohort ) or targeted sequencing ( validation cohort ) .
25636205
DNA was isolated from prechemotherapy tumor tissue and used for next generation sequencing of 178 Cancercancer associated genes ( discovery cohort ) or targeted sequencing ( validation cohort ) .
25636205
We conclude that ERBB2 missense mutations characterize a subgroup of MIBC patients with an excellent response to NAC.PATIENT SUMMARY : In this report we looked for genetic alterations that can predict the response to neoadjuvant chemotherapy ( NAC ) in Cancerbladder cancer .
25667280
PURPOSE : Approximately 1 % of Cancerlung adenocarcinomas are driven by oncogenic ROS1 rearrangement .
25667280
Eligible patients had stage IV Cancerlung adenocarcinoma , had ROS1 rearrangement according to fluorescent in situ hybridization , and had received crizotinib therapy through an individual off-label use .
25667280
We observed four patients with Diseasedisease progression , two patients with stable disease , and objective response in 24 patients , including five complete responses ( overall response rate , 80 % ; disease control rate , 86.7 % ) .
25667280
We observed four patients with disease progression , two patients with Diseasestable disease , and objective response in 24 patients , including five complete responses ( overall response rate , 80 % ; disease control rate , 86.7 % ) .
25667280
We observed four patients with disease progression , two patients with stable disease , and objective response in 24 patients , including five complete responses ( overall response rate , 80 % ; Diseasedisease control rate , 86.7 % ) .
25667280
CONCLUSION : Crizotinib was highly active at treating Cancerlung cancer in patients with a ROS1 rearrangement , suggesting that patients with lung adenocarcinomas should be tested for ROS1 .
25667280
CONCLUSION : Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement , suggesting that patients with Cancerlung adenocarcinomas should be tested for ROS1 .
25668009
BACKGROUND : CancerMalignant pleural mesothelioma ( MPM ) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed .
25668009
BACKGROUND : Malignant pleural mesothelioma ( MPM ) is a highly Canceraggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed .
25668228
CancerLung cancer patients carrying sensitive epidermal growth factor receptor ( EGFR ) mutations show dramatic responses to tyrosine kinase inhibitors ( TKIs ) .
25668228
However , the majority of patients whose Diseasedisease responds to drugs eventually develop resistance to these EGFR-TKIs .
25670080
Elucidating the determinants of aggressiveness in Cancerlethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes .
25670080
These studies reveal a GATA2-IGF2 aggressiveness axis in Cancerlethal prostate cancer and identify a therapeutic opportunity in this challenging disease .
25670080
These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this Diseasechallenging disease .
25672916
PURPOSE : Phosphatidylinositol-3-kinase I ( PI3K ) inhibition sensitizes a wide range of Cancercancer cell lines to platinum and taxane based chemotherapy .
25672916
This phase I study combines buparlisib , a pan-class 1A PI3K inhibitor , with two schedules of carboplatin and paclitaxel for patients with Canceradvanced solid tumors ( ClinicalTrials.gov , NCT01297452 ) .
25672916
The DLTs were elevated alkaline phosphatase ( n = 1 ) and Diseaseuncomplicated neutropenia ( n = 2 ) .
25672916
Among 25 patients with Diseasemeasurable disease , the confirmed objective response rate was 20 % ( one complete response , four partial responses ) .
25672916
CONCLUSION : The addition of buparlisib to carboplatin + paclitaxel was well tolerated , and preliminary activity was notable against Cancertumors with loss of PTEN expression .
25673558
We examined the impact of C and P on progression-free survival ( PFS ) , overall survival ( OS ) and overall response rate ( ORR ) in Canceradvanced colorectal cancer ( CRC ) patients who have RAS-wt and BRAF-mutant ( BRAF-mut ) status .
25673558
Overall , the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS ( HR , 0.88 ; 95 % confidence interval ( CI ) , 0.67-1 .14 ; p = 0.33 ) , OS ( HR , 0.91 ; 95 % CI , 0.62-1 .34 ; p = 0.63 ) and ORR ( AdverseOutcomerelative risk , 1.31 ; 95 % CI 0.83-2 .08 , p = 0.25 ) compared with control regimens .
25673644
BRAF mutations occur in approximately 10 % of Cancercolorectal cancers .
25673644
Although RAF inhibitor monotherapy is highly effective in CancerBRAF-mutant melanoma , response rates in BRAF-mutant colorectal cancer are poor .
25673644
Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma , response rates in CancerBRAF-mutant colorectal cancer are poor .
25673644
To identify molecular alterations driving clinical acquired resistance , we performed whole-exome sequencing on paired pretreatment and Cancerpostprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations .
25673644
To identify molecular alterations driving clinical acquired resistance , we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with CancerBRAF-mutant colorectal cancer treated with RAF inhibitor combinations .
25673644
We identified alterations in MAPK pathway genes in Cancerresistant tumors not present in matched pretreatment tumors , including KRAS amplification , BRAF amplification , and a MEK1 mutation .
25673644
We identified alterations in MAPK pathway genes in resistant tumors not present in matched Cancerpretreatment tumors , including KRAS amplification , BRAF amplification , and a MEK1 mutation .
25673644
Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in CancerBRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.SIGNIFICANCE : RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer .
25673644
Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.SIGNIFICANCE : RAF inhibitor combinations represent promising approaches in clinical development for CancerBRAF-mutant colorectal cancer .
25673644
Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling , highlighting the critical dependence of CancerBRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance .
25677871
BACKGROUND : Head and Cancerneck squamous cell carcinoma is frequently associated with aberrant epidermal growth factor receptor ( EGFR ) signaling , which contributes to tumor growth .
25677871
BACKGROUND : Head and neck squamous cell carcinoma is frequently associated with aberrant epidermal growth factor receptor ( EGFR ) signaling , which contributes to Cancertumor growth .
25677871
Here , the functional importance of EGFR ligands in relation to proliferation and sensitivity to the EGFR targeted therapy cetuximab was investigated in three Cancertongue cancer cell lines .
25677871
METHODS : The influence of epidermal growth factor ( EGF ) , amphiregulin ( AR ) , and epiregulin ( EPR ) on Cancertumor cell proliferation and cetuximab response was evaluated by the addition of recombinant human ( rh ) proteins or by siRNA mediated downregulation of the endogenous ligand production .
25677871
RESULTS : EGF downregulation suppressed the proliferation of all Cancerinvestigated tumor cell lines , whereas the response to an increased level of EGF differed between EGFR overexpressing and EGFR-non-overexpressing cell lines .
25677871
Furthermore , Cancertumor cells consistently displayed increased cetuximab resistance upon the addition of rhEGF , whereas EGF silencing was associated with an improved cetuximab response .
25677871
CONCLUSIONS : Our data suggest that the amount of EGF is a determinant of the Cancertumor cell proliferation rate and the response to cetuximab treatment in tongue cancer .
25677871
CONCLUSIONS : Our data suggest that the amount of EGF is a determinant of the tumor cell proliferation rate and the response to cetuximab treatment in Cancertongue cancer .
25688157
PURPOSE : Although ROS1 rearranged Cancernon small cell lung cancer ( NSCLC ) is sensitive to crizotinib , development of resistance is inevitable .
25688157
Here , we identified molecular alterations in Cancercrizotinib resistant tumors from two NSCLC patients with the CD74-ROS1 rearrangement , and in HCC78 cells harboring SLC34A2-ROS1 that showed resistance to crizotinib ( HCC78CR cells ) .
25688157
EXPERIMENTAL DESIGN : ROS1 kinase domain mutations were examined in Cancerfresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing .
25688157
RESULTS : The ROS1 G2032R mutation was identified in Cancercrizotinib resistant tumors from one patient .
25692060
Extramammary Paget 's Diseasedisease ( EMPD ) is a rare cancer .
25692060
Extramammary Paget 's disease ( EMPD ) is a Cancerrare cancer .
25692060
Molecular profiling of his case as well as 12 other EMPD and 8 Diseasemammary Paget disease ( MPD ) cases was completed and revealed multiple biomarker aberrations .
25692060
These findings may lead to possible therapeutic interventions targeting these pathways in a Diseasedisease with few effective treatment options .
25693012
BACKGROUND : In patients with Cancermetastatic breast cancer that is positive for human epidermal growth factor receptor 2 ( HER2 ) , progression-free survival was significantly improved after first-line therapy with pertuzumab , trastuzumab , and docetaxel , as compared with placebo , trastuzumab , and docetaxel .
25693012
METHODS : We randomly assigned patients with Cancermetastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination .
25693012
METHODS : We randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their Diseasemetastatic disease to receive the pertuzumab combination or the placebo combination .
25693012
CONCLUSIONS : In patients with CancerHER2 positive metastatic breast cancer , the addition of pertuzumab to trastuzumab and docetaxel , as compared with the addition of placebo , significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination .
25698061
CancerFibrolamellar carcinoma is a distinct subtype of hepatocellular carcinoma that predominantly affects young patients without underlying cirrhosis .
25698061
Fibrolamellar carcinoma is a distinct subtype of Cancerhepatocellular carcinoma that predominantly affects young patients without underlying cirrhosis .
25698061
A recurrent DNAJB1-PRKACA fusion has recently been reported in Cancerfibrolamellar carcinomas .
25698061
A total of 106 Cancerprimary liver tumors were studied by RT-PCR , including 26 fibrolamellar carcinomas ( 4 of which were metastases to the abdominal wall or lymph nodes ) , 25 conventional hepatocellular carcinomas , 25 cholangiocarcinomas , 25 hepatic adenomas , and 5 hepatoblastomas .
25698061
A total of 106 primary liver tumors were studied by RT-PCR , including 26 Cancerfibrolamellar carcinomas ( 4 of which were metastases to the abdominal wall or lymph nodes ) , 25 conventional hepatocellular carcinomas , 25 cholangiocarcinomas , 25 hepatic adenomas , and 5 hepatoblastomas .
25698061
A total of 106 primary liver tumors were studied by RT-PCR , including 26 fibrolamellar carcinomas ( 4 of which were metastases to the abdominal wall or lymph nodes ) , 25 Cancerconventional hepatocellular carcinomas , 25 cholangiocarcinomas , 25 hepatic adenomas , and 5 hepatoblastomas .
25698061
A total of 106 primary liver tumors were studied by RT-PCR , including 26 fibrolamellar carcinomas ( 4 of which were metastases to the abdominal wall or lymph nodes ) , 25 conventional hepatocellular carcinomas , 25 Cancercholangiocarcinomas , 25 hepatic adenomas , and 5 hepatoblastomas .
25698061
A total of 106 primary liver tumors were studied by RT-PCR , including 26 fibrolamellar carcinomas ( 4 of which were metastases to the abdominal wall or lymph nodes ) , 25 conventional hepatocellular carcinomas , 25 cholangiocarcinomas , 25 Cancerhepatic adenomas , and 5 hepatoblastomas .
25698061
A total of 106 primary liver tumors were studied by RT-PCR , including 26 fibrolamellar carcinomas ( 4 of which were metastases to the abdominal wall or lymph nodes ) , 25 conventional hepatocellular carcinomas , 25 cholangiocarcinomas , 25 hepatic adenomas , and 5 Cancerhepatoblastomas .
25698061
RT-PCR was successful in 92 % of tested Cancerfibrolamellar carcinoma cases ( 24/26 ) and the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types .
25698061
RT-PCR was successful in 92 % of tested fibrolamellar carcinoma cases ( 24/26 ) and the DNAJB1-PRKACA fusion transcript was found in all Cancerfibrolamellar carcinomas but not in other tumor types .
25698061
RT-PCR was successful in 92 % of tested fibrolamellar carcinoma cases ( 24/26 ) and the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in Cancerother tumor types .
25698061
FISH was tested in 19 Cancerfibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas , which can closely mimic fibrolamellar carcinoma .
25698061
FISH was tested in 19 fibrolamellar carcinomas and in 6 Cancerscirrhous hepatocellular carcinomas , which can closely mimic fibrolamellar carcinoma .
25698061
FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas , which can closely mimic Cancerfibrolamellar carcinoma .
25698061
Rearrangements of the PRKACA locus was seen in all 19 Cancerfibrolamellar carcinoma specimens , but in none of the scirrhous hepatocellular carcinomas .
25698061
Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens , but in none of the Cancerscirrhous hepatocellular carcinomas .
25698061
Finally , a RNA in situ hybridization strategy was positive in 7/7 successfully hybridized cases , and showed mRNA over-expression in all of the Cancerfibrolamellar carcinomas .
25698061
In addition , the stromal cells embedded in the characteristic intratumoral fibrosis of Cancerfibrolamellar carcinomas and the background liver tissues were negative for the DNAJB1-PRKACA fusion by all tested methods .
25698061
In conclusion , detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of Cancerfibrolamellar carcinoma .
25727400
CancerAnaplastic lymphoma kinase ( ALK ) is a tyrosine kinase receptor involved in both solid and hematological tumors .
25727400
Anaplastic lymphoma kinase ( ALK ) is a tyrosine kinase receptor involved in both solid and Cancerhematological tumors .
25727400
About 80 % of CancerALK positive anaplastic large-cell lymphoma ( ALCL ) cases are characterized by the t ( 2 ; 5 ) ( p23 ; q35 ) translocation , encoding for the aberrant fusion protein nucleophosmin ( NPM )-ALK , whereas 5 % of non-small-cell lung cancer ( NSCLC ) patients carry the inv ( 2 ) ( p21 ; p23 ) rearrangement , encoding for the echinoderm microtubule associated protein like 4 ( EML4 )-ALK fusion .
25727400
About 80 % of ALK positive anaplastic large-cell lymphoma ( ALCL ) cases are characterized by the t ( 2 ; 5 ) ( p23 ; q35 ) translocation , encoding for the aberrant fusion protein nucleophosmin ( NPM )-ALK , whereas 5 % of Cancernon-small-cell lung cancer ( NSCLC ) patients carry the inv ( 2 ) ( p21 ; p23 ) rearrangement , encoding for the echinoderm microtubule associated protein like 4 ( EML4 )-ALK fusion .
25727400
The ALK/c-MET/ROS inhibitor crizotinib successfully improved the treatment of DiseaseALK driven diseases .
25730903
It has been suggested that the MDM2 amplified subset of Cancerp53WT tumors might be particularly sensitive to MDM2 inhibition .
25733882
Oncogenic c-ros oncogene1 ( ROS1 ) fusion kinases have been identified in a variety of Cancerhuman cancers and are attractive targets for cancer therapy .
25733882
Oncogenic c-ros oncogene1 ( ROS1 ) fusion kinases have been identified in a variety of human cancers and are attractive targets for Cancercancer therapy .
25733882
The MET/ALK/ROS1 inhibitor crizotinib ( Xalkori , PF-02341066 ) has demonstrated promising clinical activity in CancerROS1 fusion positive non small cell lung cancer .
25733882
In vivo , PF-06463922 showed marked antitumor activity in Cancertumor models expressing FIG-ROS1 , CD74-ROS1 , and the CD74-ROS1 ( G2032R ) mutation .
25733882
Furthermore , PF-06463922 demonstrated antitumor activity in a genetically engineered mouse model of CancerFIG-ROS1 glioblastoma .
25733882
Taken together , our results indicate that PF-06463922 has potential for treating CancerROS1 fusion positive cancers , including those requiring agents with CNS penetrating properties , as well as for overcoming crizotinib resistance driven by ROS1 mutation .
25736571
OBJECTIVES : Acquired resistance mutations to Canceranaplastic lymphoma kinase ( ALK ) inhibitors such as crizotinib and alectinib have been documented in non small cell lung cancer ( NSCLC ) patients harboring ALK rearrangement ( ALK+ ) .
25736571
OBJECTIVES : Acquired resistance mutations to anaplastic lymphoma kinase ( ALK ) inhibitors such as crizotinib and alectinib have been documented in Cancernon small cell lung cancer ( NSCLC ) patients harboring ALK rearrangement ( ALK+ ) .
25759020
CancerAdvanced basal cell carcinomas ( BCCs ) frequently acquire resistance to Smoothened ( SMO ) inhibitors through unknown mechanisms .
25759020
In the presence of a SMO inhibitor , Cancertumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO .
25762343
PURPOSE : CD44 , a cell surface glycoprotein , plays important roles in the development , progression , and Cancermetastasis of various tumor types .
25762343
PURPOSE : CD44 , a cell surface glycoprotein , plays important roles in the development , progression , and metastasis of Cancervarious tumor types .
25762343
EXPERIMENTAL DESIGN : CD44 isoform expression on Cancervarious tumor cell lines was analyzed by RNASeq while data on patients with different tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study ( NCT01358903 ) .
25762343
EXPERIMENTAL DESIGN : CD44 isoform expression on various tumor cell lines was analyzed by RNASeq while data on patients with Cancerdifferent tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study ( NCT01358903 ) .
25762343
RESULTS : CD44 isoform expression , in particular expression of CD44s , is associated with HA production and predicts response to treatment with RG7356 in Cancertumor xenograft models .
25788273
CancerSporadic colorectal cancer ( CRC ) insurgence and progression depend on the activation of Wnt and beta-catenin signaling .
25788273
Moreover , we show that DKK-1 regulates Cancerseveral cancer related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 ( ALDH1A1 ) and Ral binding protein 1 associated Eps domain containing 2 ( REPS2 ) , which are involved in detoxification of chemotherapeutic agents .
25788273
Moreover , we show that DKK-1 regulates several cancer related genes including the Cancercancer stem cell marker aldehyde dehydrogenase 1A1 ( ALDH1A1 ) and Ral binding protein 1 associated Eps domain containing 2 ( REPS2 ) , which are involved in detoxification of chemotherapeutic agents .
25788273
Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in Cancertumors and correlates with decreased OS ( P = 0.001 and 0.014 ) and PFS .
25788273
In summary , our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in Cancercolorectal cancer .
25798586
CancerPeritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management .
25798586
Peritoneal mesothelioma is a rare and sometimes Cancerlethal malignancy that presents a clinical challenge for both diagnosis and management .
25798586
Recent studies have led to a better understanding of the molecular biology of Cancerperitoneal mesothelioma .
25798586
From two patients with Cancerperitoneal mesothelioma , we derived whole genome sequences , RNA expression profiles , and targeted deep sequencing data .
25798586
Molecular studies presented here provide the first reported whole genome sequences of Cancerperitoneal mesothelioma .
25798586
Mutations in Cancerknown mesothelioma related genes NF2 , CDKN2A , LATS2 , amongst others , were identified .
25798586
A hypermutated phenotype was observed in one case ( 434 vs. 18 single nucleotide variants ) and was associated with a favourable outcome despite sarcomatoid histology and Diseasemultifocal disease .
25798586
This study represents the first report of whole genome analyses of Cancerperitoneal mesothelioma , a key step in the understanding and treatment of this disease .
25798586
This study represents the first report of whole genome analyses of peritoneal mesothelioma , a key step in the understanding and treatment of this Diseasedisease .
25802883
Matching molecularly targeted therapies with Cancercancer subtype specific gene mutations is revolutionizing oncology care .
25802883
However , for Cancerrare cancers this approach is problematic due to the often poor understanding of the disease 's natural history and phenotypic heterogeneity , making treatment of these cancers a particularly unmet medical need in clinical oncology .
25802883
However , for rare cancers this approach is problematic due to the often poor understanding of the Diseasedisease 's natural history and phenotypic heterogeneity , making treatment of these cancers a particularly unmet medical need in clinical oncology .
25802883
However , for rare cancers this approach is problematic due to the often poor understanding of the disease 's natural history and phenotypic heterogeneity , making treatment of these Cancercancers a particularly unmet medical need in clinical oncology .
25802883
DiseaseAdvanced Sezary syndrome ( SS ) , an aggressive , exceedingly rare variant of cutaneous T-cell lymphoma ( CTCL ) is a prototypical example of a rare cancer .
25802883
Advanced Sezary syndrome ( SS ) , an aggressive , exceedingly rare variant of Cancercutaneous T-cell lymphoma ( CTCL ) is a prototypical example of a rare cancer .
25802883
Advanced Sezary syndrome ( SS ) , an aggressive , exceedingly rare variant of cutaneous T-cell lymphoma ( CTCL ) is a prototypical example of a Cancerrare cancer .
25802883
Through whole genome and RNA sequencing ( RNA-seq ) of a SS patient 's Cancertumor we discovered a highly expressed gene fusion between CTLA4 ( cytotoxic T lymphocyte antigen 4 ) and CD28 ( cluster of differentiation 28 ) , predicting a novel stimulatory molecule on the surface of tumor T cells .
25802883
Through whole genome and RNA sequencing ( RNA-seq ) of a SS patient 's tumor we discovered a highly expressed gene fusion between CTLA4 ( cytotoxic T lymphocyte antigen 4 ) and CD28 ( cluster of differentiation 28 ) , predicting a novel stimulatory molecule on the surface of Cancertumor T cells .
25802883
Our findings suggest a novel driver mechanism for SS , and Cancercancer in general , and exemplify an emerging model of cancer treatment using exploratory genomic analysis to identify a personally targeted treatment option when conventional therapies are exhausted .
25802883
Our findings suggest a novel driver mechanism for SS , and cancer in general , and exemplify an emerging model of Cancercancer treatment using exploratory genomic analysis to identify a personally targeted treatment option when conventional therapies are exhausted .
25847936
PURPOSE : The identification of patients with Cancermetastatic triple negative breast cancer ( mTNBC ) who are expected to benefit from platinum based chemotherapy is of interest .
25847936
Secondary and exploratory end points included Diseasetoxicity assessment , RR in cisplatin versus carboplatin , and RR in molecularly defined subgroups , including BRCA1/2 mutation carriers .
25847936
In patients without BRCA1/2 mutations ( n = 66 ) , exploratory analyses showed that a BRCA like genomic instability signature ( n = 32 ) discriminated responding and Cancernonresponding tumors ( mean homologous recombination deficiency-loss of heterozygosity and homologous recombination deficiency-large-scale state transitions [ HRD-LOH and HRD-LST ] scores were 12.68 and 5.11 , respectively ) , whereas predefined analysis by p63 and p73 expression status ( n = 61 ) , p53 and PIK3CA mutation status ( n = 53 ) , or PAM50 gene expression subtype ( n = 55 ) did not .
25847936
Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations , and two of them had increased Cancertumor HRD-LOH and HRD-LST scores .
25847936
A measure of Cancertumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents .
25852058
CancerDermatofibrosarcoma protuberans ( DFSP ) is an aggressive PDGFB dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences .
25852058
Dermatofibrosarcoma protuberans ( DFSP ) is an Canceraggressive PDGFB dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences .
25852058
Some DFSP progress to a higher-grade fibrosarcomatous form , with rapid growth and increased AdverseOutcomerisk of metastasis .
25852058
Some DFSP progress to a higher-grade fibrosarcomatous form , with rapid growth and increased risk of Cancermetastasis .
25852058
In vivo treatment of DFSP105 with PD-0332991 ( 150 mg/kg ) inhibited xenograft growth in mice , in comparison with imatinib treated or Cancer-untreated tumors .
25853747
BACKGROUND : MYD88 ( L265P ) and CXCR4 ( WHIM ) mutations are highly prevalent in Waldenstrom 's Diseasemacroglobulinemia .
25853747
METHODS : We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenstrom 's Diseasemacroglobulinemia who had received at least one previous treatment , and we investigated the effect of MYD88 and CXCR4 mutations on outcomes .
25853747
Ibrutinib at a daily dose of 420 mg was administered orally until Diseasedisease progression or the development of unacceptable toxic effects .
25853747
Treatment related toxic effects of grade 2 or higher included Diseaseneutropenia ( in 22 % of the patients ) and thrombocytopenia ( in 14 % ) , which were more common in heavily pretreated patients ; postprocedural bleeding ( in 3 % ) ; epistaxis associated with the use of fish-oil supplements ( in 3 % ) ; and atrial fibrillation associated with a history of arrhythmia ( 5 % ) .
25853747
Treatment related toxic effects of grade 2 or higher included neutropenia ( in 22 % of the patients ) and Diseasethrombocytopenia ( in 14 % ) , which were more common in heavily pretreated patients ; postprocedural bleeding ( in 3 % ) ; epistaxis associated with the use of fish-oil supplements ( in 3 % ) ; and atrial fibrillation associated with a history of arrhythmia ( 5 % ) .
25853747
CONCLUSIONS : Ibrutinib was highly active , associated with durable responses , and safe in pretreated patients with Waldenstrom 's Diseasemacroglobulinemia .
25855885
IMPORTANCE : The PIK3CA mutation is one of the most common mutations in head and Cancerneck squamous cell carcinoma ( HNSCC ) .
25855885
Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of CancerPI3K-overactive HNSCC tumors .
25862853
BACKGROUND : A recent pooled analysis of the LUX-LUNG3 and LUX-LUNG6 trials suggested that afatinib ( an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor ( EGFR-TKI ) ) is especially effective against Cancernon small cell lung cancer ( NSCLC ) carrying an EGFR exon 19 deletion .
25878190
BACKGROUND : Mesenchymal and Cancermetaplastic breast cancers ( MpBCs ) are often triple negative ( TNBC ) , and chemo-refractory , and can harbor phosphoinositide 3-kinase ( PI3kinase ) alterations ; thus , therapy with mTor inhibitors may demonstrate activity .
25878190
An additional two patients achieved Diseasestable disease ( SD ) > = 6 months [ total SD > = 6 months/CR/PR = 8 ( 33 % ) ] .
25883215
Based on a series of basic , preclinical and clinical studies , the Poly ( ADP-ribose ) Polymerase 1 ( PARP1 ) inhibitor , olaparib , has recently been approved for use in Cancerovarian cancer patients with BRCA1 or BRCA2 mutations .
25883215
By identifying novel predictive biomarkers of Cancertumour cell sensitivity to olaparib , it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup .
25883215
We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in Cancerbreast cancer cell line models and that defective homologous recombination ( HR ) DNA repair is the likely cause .
25883215
This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of Cancertumour cells to PARP inhibitors .
25892145
BACKGROUND : Patients with recurrent or Cancermetastatic squamous-cell carcinoma of the head and neck ( HNSCC ) progressing after first-line platinum regimens have a poor prognosis and few treatment options .
25892145
BACKGROUND : Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck ( HNSCC ) progressing after first-line platinum regimens have a AdverseOutcomepoor prognosis and few treatment options .
25892145
We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib ( 40 mg/day ) or intravenous methotrexate ( 40 mg/m ( 2 ) per week ) , stratified by ECOG performance status and previous EGFR targeted antibody therapy for recurrent or Diseasemetastatic disease .
25892145
Clinicians and patients were not masked to treatment allocation ; independent review of Cancertumour response was done in a blinded manner .
25892145
The most frequent grade 3 or 4 drug related adverse events were rash or acne ( 31 [ 10 % ] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group ) , diarrhoea ( 30 [ 9 % ] vs three [ 2 % ] ) , Diseasestomatitis ( 20 [ 6 % ] vs 13 [ 8 % ] ) , fatigue ( 18 [ 6 % ] vs five [ 3 % ] ) , and neutropenia ( 1 [ < 1 % ] vs 11 [ 7 % ] ) ; serious adverse events occurred in 44 ( 14 % ) of afatinib treated patients and 18 ( 11 % ) of methotrexate treated patients .
25892145
The most frequent grade 3 or 4 drug related adverse events were rash or acne ( 31 [ 10 % ] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group ) , diarrhoea ( 30 [ 9 % ] vs three [ 2 % ] ) , stomatitis ( 20 [ 6 % ] vs 13 [ 8 % ] ) , fatigue ( 18 [ 6 % ] vs five [ 3 % ] ) , and Diseaseneutropenia ( 1 [ < 1 % ] vs 11 [ 7 % ] ) ; serious adverse events occurred in 44 ( 14 % ) of afatinib treated patients and 18 ( 11 % ) of methotrexate treated patients .
25899785
BACKGROUND : HER2 mutations and amplifications have been identified as oncogenic drivers in Cancerlung cancers .
25899785
Here , we studied dacomitinib in patients with HER2-mutant or amplified Cancerlung cancers .
25899785
PATIENTS AND METHODS : As a prespecified cohort of a phase II study , we included patients with Cancerstage IIIB/IV lung cancers with HER2 mutations or amplification .
25899785
End points included partial response rate , overall survival , and Diseasetoxicity .
25899785
RESULTS : We enrolled 30 patients with HER2-mutant ( n = 26 , all in exon 20 including 25 insertions and 1 missense mutation ) or HER2 amplified Cancerlung cancers ( n = 4 ) .
25899785
Three of 26 patients with Cancertumors harboring HER2 exon 20 mutations [ 12 % ; 95 % confidence interval ( CI ) 2 % to 30 % ] had partial responses lasting 3+ , 11 , and 14 months .
25899785
No partial responses occurred in four patients with Cancertumors with HER2 amplifications .
25899785
DiseaseTreatment related toxicities included diarrhea ( 90 % ; grade 3/4 : 20 %/3 % ) , dermatitis ( 73 % ; grade 3/4 : 3 %/0 % ) , and fatigue ( 57 % ; grade 3/4 : 3 %/0 % ) .
25899785
Treatment related toxicities included diarrhea ( 90 % ; grade 3/4 : 20 %/3 % ) , Diseasedermatitis ( 73 % ; grade 3/4 : 3 %/0 % ) , and fatigue ( 57 % ; grade 3/4 : 3 %/0 % ) .
25899785
CONCLUSIONS : Dacomitinib produced objective responses in patients with Cancerlung cancers with specific HER2 exon 20 insertions .
25899785
This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2 targeted agents in specific HER2 driven Cancerlung cancers .
25900183
The stratification of Cancerbreast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect .
25900183
The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in Cancerbreast cancer , to evaluate TFF3 as a biomarker of endocrine response , and to investigate TFF3 function .
25900183
TFF3 was induced by oestrogen , and its induction was inhibited by antioestrogens , tamoxifen , 4-hydroxytamoxifen and fulvestrant in Canceroestrogen responsive breast cancer cells .
25900183
The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in Cancerbreast tumours ( Pearson 's coefficient = 0.762 , P = 0.000 ) .
25900183
TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy , degree of response and duration of response in Cancerunstratified metastatic breast cancer patients ( P = 0.000 , P = 0.002 and P = 0.002 respectively ) .
25900183
TFF3 stimulated migration and invasion of Cancerbreast cancer cells .
25900183
In conclusion , TFF3 expression is associated with response to endocrine therapy , and outperforms oestrogen receptor , progesterone receptor and TFF1 as an independent biomarker , possibly because it mediates the malign effects of oestrogen on invasion and Cancermetastasis .
25910840
BACKGROUND : Promoter methylation of O ( 6 )-methylguanine-DNA methyltransferase ( MGMT ) is an important predictive biomarker in Cancerglioblastoma .
25910840
The T variant of the MGMT promoter-enhancer single nucleotide polymorphism ( SNP ; rs16906252 ) has been associated with the presence of MGMT promoter methylation in Cancerother cancers .
25910840
We examined the association of the T allele of rs16906252 with Cancerglioblastoma development , tumor MGMT methylation , MGMT protein expression , and survival outcomes .
25910840
We examined the association of the T allele of rs16906252 with glioblastoma development , Cancertumor MGMT methylation , MGMT protein expression , and survival outcomes .
25910840
METHODS : Two independent temozolomide treated Cancerglioblastoma cohorts-one Australian ( Australian Genomics and Clinical Outcomes of Glioma , n = 163 ) and the other American ( University of California Los Angeles and Kaiser Permanente Los Angeles , n = 159 )-were studied .
25910840
METHODS : Two independent temozolomide treated glioblastoma cohorts-one Australian ( Australian Genomics and Clinical Outcomes of CancerGlioma , n = 163 ) and the other American ( University of California Los Angeles and Kaiser Permanente Los Angeles , n = 159 )-were studied .
25910840
METHODS : Two independent temozolomide treated glioblastoma cohorts-one Australian ( Australian Genomics and Clinical Outcomes of Glioma , n = 163 ) and the other American ( University of DiseaseCalifornia Los Angeles and Kaiser Permanente Los Angeles , n = 159 )-were studied .
25910840
Additionally , we compared the incidence of the T allele between Cancerglioblastoma cases and matched controls to assess whether it was a risk factor for developing MGMT methylated glioblastoma .
25910840
Additionally , we compared the incidence of the T allele between glioblastoma cases and matched controls to assess whether it was a AdverseOutcomerisk factor for developing MGMT methylated glioblastoma .
25910840
Additionally , we compared the incidence of the T allele between glioblastoma cases and matched controls to assess whether it was a risk factor for developing MGMT methylated Cancerglioblastoma .
25910840
RESULTS : Carriage of the T allele of the rs16906252 SNP was associated with both MGMT methylation and low MGMT protein expression and predicted significantly longer survival in temozolomide treated patients with both MGMT methylated and nonmethylated Cancerglioblastoma .
25910840
Carriage of the T allele was associated with a significantly AdverseOutcomeelevated risk of developing glioblastoma ( adjusted odds ratio , 1.96 ; P = .013 ) , increasing further when glioblastoma was classified by the presence of MGMT methylation ( adjusted odds ratio , 2.86 ; P = .001 ) .
25910840
Carriage of the T allele was associated with a significantly elevated risk of developing Cancerglioblastoma ( adjusted odds ratio , 1.96 ; P = .013 ) , increasing further when glioblastoma was classified by the presence of MGMT methylation ( adjusted odds ratio , 2.86 ; P = .001 ) .
25910840
Carriage of the T allele was associated with a significantly elevated risk of developing glioblastoma ( adjusted odds ratio , 1.96 ; P = .013 ) , increasing further when Cancerglioblastoma was classified by the presence of MGMT methylation ( adjusted odds ratio , 2.86 ; P = .001 ) .
25910840
CONCLUSIONS : The T allele of the rs16906252 SNP is a key determinant in the acquisition of MGMT methylation in Cancerglioblastoma .
25910840
Temozolomide treated patients with the rs16906252 T genotype have better survival , irrespective of Cancertumor methylation status .
25923549
BACKGROUND : The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors in patients who have Cancerlung cancer with an EGFR mutation ( EGFR mutated lung cancer ) .
25923549
BACKGROUND : The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation ( EGFR mutated Cancerlung cancer ) .
25923549
METHODS : We administered AZD9291 at doses of 20 to 240 mg once daily in patients with Canceradvanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors .
25923549
METHODS : We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented Diseasedisease progression after previous treatment with EGFR tyrosine kinase inhibitors .
25923549
In the expansion cohorts , Cancerprestudy tumor biopsies were required for central determination of EGFR T790M status .
25923549
The Canceroverall objective tumor response rate was 51 % ( 95 % confidence interval [ CI ] , 45 to 58 ) .
25923549
CONCLUSIONS : AZD9291 was highly active in patients with Cancerlung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors .
25923549
CONCLUSIONS : AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had Diseasedisease progression during prior therapy with EGFR tyrosine kinase inhibitors .
25923550
BACKGROUND : CancerNon-small-cell lung cancer ( NSCLC ) with a mutation in the gene encoding epidermal growth factor receptor ( EGFR ) is sensitive to approved EGFR inhibitors , but resistance develops , mediated by the T790M EGFR mutation in most cases .
25923550
METHODS : In this phase 1-2 study , we administered rociletinib to patients with EGFR mutated NSCLC who had Diseasedisease progression during previous treatment with an existing EGFR inhibitor .
25923550
In the expansion ( phase 2 ) part of the study , patients with DiseaseT790M positive disease received rociletinib at a dose of 500 mg twice daily , 625 mg twice daily , or 750 mg twice daily .
25923550
CancerTumor biopsies to identify T790M were performed during screening .
25923550
The only common dose limiting adverse event was Diseasehyperglycemia .
25923550
In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose , the objective response rate among the 46 patients with DiseaseT790M positive disease who could be evaluated was 59 % ( 95 % confidence interval [ CI ] , 45 to 73 ) , and the rate among the 17 patients with T790M negative disease who could be evaluated was 29 % ( 95 % CI , 8 to 51 ) .
25923550
In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose , the objective response rate among the 46 patients with T790M positive disease who could be evaluated was 59 % ( 95 % confidence interval [ CI ] , 45 to 73 ) , and the rate among the 17 patients with DiseaseT790M negative disease who could be evaluated was 29 % ( 95 % CI , 8 to 51 ) .
25924824
BACKGROUND : Chemoradiation therapy ( CRT ) is one of the most useful treatments for Canceresophageal squamous cell carcinoma ( ESCC ) .
25924824
METHODS : We immunohistochemically investigated the expression of Aurora-A in biopsy specimens of Canceruntreated primary tumors of 78 patients with ESCC and determined the relationship between Aurora-A levels and patient responses to CRT , which consisted of 5-fluorouracil plus cisplatin and 40Gy of radiation .
25924824
RESULTS : CancerTumors were judged as Aurora-A positive when more than 10 % of the cancer cells displayed a distinct positive nuclear anti-Aurora-A immunoreaction by immunohistochemical evaluation .
25924824
RESULTS : Tumors were judged as Aurora-A positive when more than 10 % of the Cancercancer cells displayed a distinct positive nuclear anti-Aurora-A immunoreaction by immunohistochemical evaluation .
25924824
The Cancertumors of 46 of 78 patients ( 58.9 % ) displayed positive expression of Aurora-A .
25924824
In terms of clinical response the percentage of patients showing complete response ( CR ) , incomplete response and Diseasestable disease of primary lesion ( IR/SD ) , and progressive disease ( PD ) was 19.2 , 69.2 , and 11.5 % , respectively .
25924824
In terms of clinical response the percentage of patients showing complete response ( CR ) , incomplete response and stable disease of primary lesion ( IR/SD ) , and Diseaseprogressive disease ( PD ) was 19.2 , 69.2 , and 11.5 % , respectively .
25924824
In terms of histological response the Cancertumor grade of the 41 patients who underwent surgery was as follows : grade 1 , 48.8 % ; grade 2 , 29.2 % ; grade 3 , 22.0 % .
25924824
CRT was effective for patients who had Aurora-A ( + ) Cancertumors ( clinically : P = 0.0003 , histologically : P = 0.036 ) .
25924824
CONCLUSIONS : Our results suggest that Aurora-A expression in biopsy specimens of Cancerprimary tumors is associated with CRT efficacy in patients with ESCC .
25928036
Paclitaxel ( PTX ) is a widely used chemotherapeutic drug effective against Cancernumerous cancers .
25928036
We demonstrated that PDCD4 is a cell-cycle regulated protein and that changes in its abundance are sufficient to alter PTX sensitivity in Cancermultiple human cancer cell lines .
25928036
Lastly , high levels of PDCD4 in Cancerlung cancer tissues are positively correlated with the longer overall survival time of the examined lung cancer patients with PTX involved adjuvant therapy .
25928036
Lastly , high levels of PDCD4 in lung cancer tissues are positively correlated with the longer overall survival time of the Cancerexamined lung cancer patients with PTX involved adjuvant therapy .
25928036
Therefore , our proteomic screen for paclitaxel targets not only provided novel insight into the cellular resistance to paclitaxel via the PDCD4-mitotic exit regulation axis , but also offered a predictive biomarker for paclitaxel based personalized chemotherapy in the treatment of Cancerlung cancer .
25939061
Here we studied cell-free plasma DNA ( cfDNA ) collected from subjects with Canceradvanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) AZD9291 .
25939061
Here we studied cell-free plasma DNA ( cfDNA ) collected from subjects with advanced lung cancer whose Cancertumors had developed resistance to the epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) AZD9291 .
25939061
Our findings provide insight into the diversity of mechanisms through which Cancertumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation .
25939761
Glioblastomas ( GBM ) are devastating Cancertumors in which there has been little clinical improvement in the last decades .
25939761
However , the results obtained with first generation tyrosine kinase inhibitors have been disappointing with no clear predictive markers of Cancertumor response .
25939761
Moreover , systemic administration of dacomitinib strongly impaired the in vivo Cancertumor growth rate of these EGFR amplified cell lines , with a decrease in the expression of stem cell related markers .
25968887
Decitabine , a Cancercancer therapeutic that inhibits DNA methylation , produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker .
25968887
Decitabine , a cancer therapeutic that inhibits DNA methylation , produces variable antitumor response rates in patients with Cancersolid tumors that might be leveraged clinically with identification of a predictive biomarker .
25968887
In this study , we profiled the response of human ovarian , Cancermelanoma , and breast cancer cells treated with decitabine , finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity .
25968887
In this study , we profiled the response of human ovarian , melanoma , and Cancerbreast cancer cells treated with decitabine , finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity .
25968887
Further , we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and Cancerhigh-grade serous ovarian cancer cells .
25968887
Pretreatment with decitabine decreased the cytotoxic activity of MEK inhibitors in CancerKRAS-mutant ovarian cancer cells , with reciprocal downregulation of DNMT1 and MEK and ERK phosphorylation .
25968887
In a xenograft model of CancerKRAS-mutant ovarian cancer , combining decitabine and navitoclax heightened antitumor activity beyond administration of either compound alone .
25968887
Our results define the RAS/MEK/DNMT1 pathway as a determinant of sensitivity to DNA methyltransferase inhibition , specifically implicating KRAS status as a biomarker of drug response in Cancerovarian cancer .
25970771
Histone deacetylases are important targets for Cancercancer therapeutics , but their regulation is poorly understood .
25970771
Our data show coordinated transcription of HDAC1 and HDAC2 in Cancerlung cancer cell lines , but suggest HDAC2 protein expression is cell-context specific .
25970771
BAP1 loss-of-function is increasingly reported in Cancercancers including thoracic malignancies , with frequent mutation in malignant pleural mesothelioma .
25970771
BAP1 loss-of-function is increasingly reported in cancers including Cancerthoracic malignancies , with frequent mutation in malignant pleural mesothelioma .
25970771
BAP1 loss-of-function is increasingly reported in cancers including thoracic malignancies , with frequent mutation in Cancermalignant pleural mesothelioma .
25970771
Endogenous HDAC2 directly correlates with BAP1 across a panel of Cancerlung cancer cell lines , and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation .
25970771
Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines , and is downregulated in Cancermesothelioma cell lines with genetic BAP1 inactivation .
25970771
However , Cancerother established mesothelioma cell lines with low endogenous HDAC2 have adapted to become more resistant to HDAC inhibition .
25970771
Our work establishes a mechanism by which BAP1 loss alters sensitivity of Cancercancer cells to HDAC inhibitors .
25971938
Recurrent somatic splice site alterations at MET exon 14 ( METex14 ) that result in exon skipping and MET activation have been characterized , but their full diversity and prevalence across Cancertumor types are unknown .
25971938
Here , we report analysis of Cancertumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations ( 0.6 % ) , including 126 distinct sequence variants .
25971938
METex14 mutations are detected most frequently in Cancerlung adenocarcinoma ( 3 % ) , but also frequently in other lung neoplasms ( 2.3 % ) , brain glioma ( 0.4 % ) , and tumors of unknown primary origin ( 0.4 % ) .
25971938
METex14 mutations are detected most frequently in lung adenocarcinoma ( 3 % ) , but also frequently in other lung neoplasms ( 2.3 % ) , Cancerbrain glioma ( 0.4 % ) , and tumors of unknown primary origin ( 0.4 % ) .
25971938
METex14 mutations are detected most frequently in lung adenocarcinoma ( 3 % ) , but also frequently in other lung neoplasms ( 2.3 % ) , brain glioma ( 0.4 % ) , and Cancertumors of unknown primary origin ( 0.4 % ) .
25971938
We also report three new patient cases with METex14 alterations in lung or Cancerhistiocytic sarcoma tumors that showed durable response to two different MET targeted therapies .
25971938
Patients whose Cancertumors harbored these alterations derived meaningful clinical benefit from MET inhibitors .
25971939
We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV Cancerlung adenocarcinomas harboring mutations leading to MET exon 14 skipping , highlighting a new therapeutic strategy for the 4 % of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.SIGNIFICANCE : Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4 % of lung adenocarcinomas .
25971939
We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping , highlighting a new therapeutic strategy for the 4 % of Cancerlung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.SIGNIFICANCE : Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4 % of lung adenocarcinomas .
25971939
We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping , highlighting a new therapeutic strategy for the 4 % of lung adenocarcinoma patients whose Cancertumors harbor this previously underappreciated genetic alteration.SIGNIFICANCE : Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4 % of lung adenocarcinomas .
25971939
We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping , highlighting a new therapeutic strategy for the 4 % of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.SIGNIFICANCE : Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4 % of Cancerlung adenocarcinomas .
25971939
We report responses to the MET inhibitors crizotinib and cabozantinib in patients with Cancerlung adenocarcinomas harboring MET exon 14 splice site mutations , identifying a new potential therapeutic target in this disease .
25971939
We report responses to the MET inhibitors crizotinib and cabozantinib in patients with lung adenocarcinomas harboring MET exon 14 splice site mutations , identifying a new potential therapeutic target in this Diseasedisease .
25973082
OBJECTIVE : Bevacizumab is the only anti-angiogenic agent approved in first-line therapy for Cancermetastatic colorectal cancer ( mCRC ) .
25982012
In-frame fusion KIF5B ( the-kinesin-family-5B-gene )-RET transcripts have been characterized in 1-2 % of Cancernon small cell lung cancers and are known oncogenic drivers .
25982012
In vitro studies have shown that vandetanib is a high-affinity substrate of Cancerbreast cancer resistance protein ( Bcrp1 and Abcg2 ) but is not transported by P-glycoprotein ( P-gp ) , limiting its blood-brain barrier penetration .
25982012
We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET rearranged Cancerlung cancer and the first evidence of blood-brain barrier penetration .
25982012
A 74-year-old female with Cancerprogressive adenocarcinoma of the lung ( wild-type EGFR and no ALK rearrangement ) presented for therapy options .
25982012
Because of Diseaseprogressive disease in the brain , she was enrolled in a clinical trial with vandetanib and everolimus ( NCT01582191 ) .
25982012
After two cycles of therapy a repeat MRI brain showed a decrease in the Diseaseintracranial disease burden and PET/CT showed systemic response as well .
25982282
Signal transducer and activator of transcription 3 ( STAT3 ) overactivation is a common event in Cancermany cancers , including head and neck squamous cell carcinoma ( HNSCC ) , where STAT3 represents a promising therapeutic target .
25982282
Signal transducer and activator of transcription 3 ( STAT3 ) overactivation is a common event in many cancers , including head and Cancerneck squamous cell carcinoma ( HNSCC ) , where STAT3 represents a promising therapeutic target .
25982282
HNSCC is not characterized by frequent kinase mutations , in contrast to some Cancermalignancies where mutational activation of kinases upstream of STAT3 is common .
25982282
Here we first analyzed The CancerCancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers , including HNSCC ( 60.1 % of tumors analyzed ) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression .
25982282
Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in Cancerseveral cancers , including HNSCC ( 60.1 % of tumors analyzed ) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression .
25982282
Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers , including HNSCC ( 60.1 % of Cancertumors analyzed ) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression .
25982282
These findings were confirmed in an independent cohort of CancerHNSCC tumors by methylation specific PCR and immunohistochemistry .
25989278
BACKGROUND : CancerMetastatic colorectal cancer ( mCRC ) that harbours a BRAF V600E mutation ( BRAF MT ) is associated with poorer outcomes .
25989278
For CancerRAS WT/BRAF MT tumours , the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 ( 95 % CI ; 0.67-1 .41 ) , whereas the hazard ratio was 0.81 ( 95 % CI ; 0.70-0 .95 ) for RAS WT/BRAF WT tumours .
25989278
For RAS WT/BRAF MT tumours , the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 ( 95 % CI ; 0.67-1 .41 ) , whereas the hazard ratio was 0.81 ( 95 % CI ; 0.70-0 .95 ) for CancerRAS WT/BRAF WT tumours .
25989278
Regarding PFS benefit with anti-EGFR mAbs , the hazard ratio was 0.86 ( 95 % CI ; 0.61-1 .21 ) for CancerRAS WT/BRAF MT tumours as compared with 0.62 ( 95 % CI ; 0.50-0 .77 ) for RAS WT/BRAF WT tumours ( test of interaction , P = 0.07 ) .
25989278
Regarding PFS benefit with anti-EGFR mAbs , the hazard ratio was 0.86 ( 95 % CI ; 0.61-1 .21 ) for RAS WT/BRAF MT tumours as compared with 0.62 ( 95 % CI ; 0.50-0 .77 ) for CancerRAS WT/BRAF WT tumours ( test of interaction , P = 0.07 ) .
26000489
Toward development of a precision medicine framework for metastatic , Cancercastration resistant prostate cancer ( mCRPC ) , we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals .
26000489
Toward development of a precision medicine framework for metastatic , castration resistant prostate cancer ( mCRPC ) , we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or Cancersoft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals .
26000489
Aberrations of AR , ETS genes , TP53 , and PTEN were frequent ( 40 %-60% of cases ) , with TP53 and AR alterations enriched in mCRPC compared to Cancerprimary prostate cancer .
26000489
Moreover , aberrations of BRCA2 , BRCA1 , and ATM were observed at substantially higher frequencies ( 19.3 % overall ) compared to those in Cancerprimary prostate cancers .
26000489
89 % of affected individuals harbored a clinically actionable aberration , including 62.7 % with aberrations in AR , 65 % in Cancerother cancer related genes , and 8 % with actionable pathogenic germline alterations .
26015511
PURPOSE : FGFR1 copy-number gain ( CNG ) occurs in head and Cancerneck squamous cell cancers ( HNSCC ) and is used for patient selection in FGFR specific inhibitor clinical trials .
26015511
This study explores FGFR1 mRNA and protein levels in HNSCC cell lines , Cancerprimary tumors , and patient derived xenografts ( PDX ) as predictors of sensitivity to the FGFR inhibitor , NVP-BGJ398 .
26015511
HNSCC PDXs ( n = 39 ) were submitted to FGFR1 copy-number detection and mRNA assays to identify Cancerputative FGFR1 dependent tumors .
26015511
Thirty-one percent of Cancerprimary HNSCC tumors expressed FGFR1 mRNA , 18 % exhibited FGFR1 CNG , 35 % of amplified tumors were also positive for FGFR1 mRNA .
26015511
Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA , 18 % exhibited FGFR1 CNG , 35 % of amplified Cancertumors were also positive for FGFR1 mRNA .
26015511
The Cancernonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398 .
26027660
AIM : Previous study has shown that Cancerendometrial cancers with LKB1 inactivation are highly responsive to mTOR inhibitors .
26027660
In this study we examined the effect of LKB1 gene status on mTOR inhibitor responses in Cancernon small cell lung cancer ( NSCLC ) cells .
26027660
METHODS : CancerLung cancer cell lines Calu-1 , H460 , H1299 , H1792 , and A549 were treated with the mTOR inhibitors rapamycin or everolimus ( RAD001 ) .
26033044
A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with Canceradvanced ovarian cancer .
26046389
Epidermal growth factor receptor ( EGFR ) is frequently overexpressed in head and Cancerneck squamous cell carcinoma ( HNSCC ) and cetuximab , a monoclonal antibody targeting this receptor , is widely used to treat these patients .
26046389
In the HNSCC genomic dataset obtained from The CancerCancer Genome Atlas , SMAD4 was altered in 20/279 ( 7 % ) of HNSCC via homozygous deletion , and nonsense , missense , and silent mutations .
26046389
When SMAD4 expression was compared with respect to human papillomavirus ( HPV ) status , CancerHPV positive tumors had higher expression compared to HPV negative tumors .
26046389
When SMAD4 expression was compared with respect to human papillomavirus ( HPV ) status , HPV positive tumors had higher expression compared to CancerHPV negative tumors .
26051236
BACKGROUND : Most patients with Cancernon-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21 , or both ( ie , common mutations ) .
26051236
However , a subset of patients ( 10 % ) with mutations in EGFR have Cancertumours that harbour uncommon mutations .
26051236
There is a paucity of data regarding the sensitivity of these Cancertumours to EGFR inhibitors .
26051236
Here we present data for the activity of afatinib in patients with Canceradvanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations .
26051236
Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have Cancertumours harbouring uncommon EGFR mutations .
26051236
METHODS : In this post-hoc analysis , we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation positive advanced ( stage IIIb-IV ) Cancerlung adenocarcinomas who were given afatinib in a single group phase 2 trial ( LUX-Lung 2 ) , and randomised phase 3 trials ( LUX-Lung 3 and LUX-Lung 6 ) .
26051236
INTERPRETATION : Afatinib was active in Cancernon-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations , especially Gly719Xaa , Leu861Gln , and Ser768Ile , but less active in other mutations types .
26051236
These data could help inform clinical decisions for patients with Cancernon-small-cell lung cancer harbouring uncommon EGFR mutations .
26057002
DNA damaging agents are commonly used for first-line chemotherapy of Canceradvanced non small cell lung cancer ( NSCLC ) .
26061751
BACKGROUND : Diffuse low-grade and Cancerintermediate-grade gliomas ( which together make up the lower-grade gliomas , World Health Organization grades II and III ) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class .
26061751
BACKGROUND : Diffuse low-grade and intermediate-grade gliomas ( which together make up the Cancerlower-grade gliomas , World Health Organization grades II and III ) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class .
26061751
Some are indolent ; others quickly progress to Cancerglioblastoma .
26061751
Mutations in IDH , TP53 , and ATRX and codeletion of chromosome arms 1p and 19q ( 1p/19q codeletion ) have been implicated as clinically relevant markers of Cancerlower-grade gliomas .
26061751
METHODS : We performed genomewide analyses of 293 Cancerlower-grade gliomas from adults , incorporating exome sequence , DNA copy number , DNA methylation , messenger RNA expression , microRNA expression , and targeted protein expression .
26061751
RESULTS : Unsupervised clustering of mutations and data from RNA , DNA-copy-number , and DNA methylation platforms uncovered concordant classification of three robust , nonoverlapping , prognostically significant subtypes of Cancerlower-grade glioma that were captured more accurately by IDH , 1p/19q , and TP53 status than by histologic class .
26061751
Patients who had Cancerlower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes .
26061751
Their Cancergliomas harbored mutations in CIC , FUBP1 , NOTCH1 , and the TERT promoter .
26061751
Nearly all Cancerlower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 ( 94 % ) and ATRX inactivation ( 86 % ) .
26061751
The large majority of Cancerlower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma .
26061751
The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in Cancerprimary glioblastoma .
26061751
CONCLUSIONS : The integration of genomewide data from multiple platforms delineated three molecular classes of Cancerlower-grade gliomas that were more concordant with IDH , 1p/19q , and TP53 status than with histologic class .
26061751
CancerLower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation .
26061751
CancerMost lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma .
26061751
Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to Cancerglioblastoma .
26072686
( 3 ) Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center , University of DiseaseCalifornia San Francisco , San Francisco , CA , USA .
26086854
BACKGROUND : The potential predictive role of programmed death-ligand-1 ( PD-L1 ) expression on Cancertumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research .
26086854
BACKGROUND : The potential predictive role of programmed death-ligand-1 ( PD-L1 ) expression on tumor cells in the context of Cancersolid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research .
26086854
METHODS : Overall response rate ( ORR ) was extracted from phase I-III trials investigating nivolumab , pembrolizumab and MPDL3280A for Canceradvanced melanoma , non small cell lung cancer ( NSCLC ) and genitourinary cancer , and cumulated by adopting a fixed and random-effect model with 95 % confidence interval ( CI ) .
26086854
METHODS : Overall response rate ( ORR ) was extracted from phase I-III trials investigating nivolumab , pembrolizumab and MPDL3280A for advanced melanoma , Cancernon small cell lung cancer ( NSCLC ) and genitourinary cancer , and cumulated by adopting a fixed and random-effect model with 95 % confidence interval ( CI ) .
26086854
METHODS : Overall response rate ( ORR ) was extracted from phase I-III trials investigating nivolumab , pembrolizumab and MPDL3280A for advanced melanoma , non small cell lung cancer ( NSCLC ) and Cancergenitourinary cancer , and cumulated by adopting a fixed and random-effect model with 95 % confidence interval ( CI ) .
26086854
Interaction test according to Cancertumor PD-L1 was accomplished .
26086854
A sensitivity analysis according to adopted drug , Cancertumor type , PD-L1 cut-off and treatment line was performed .
26086854
A significant interaction ( p < 0.0001 ) according to Cancertumor PD-L1 expression was found in the overall sample with an ORR of 34.1 % ( 95 % CI 27.6-41 .3 % ) in the PD-L1 positive and 19.9 % ( 95 % CI 15.4-25 .3 % ) in the PD-L1 negative population .
26086854
A significant difference in activity of 22.8 % and 8.7 % according to PD-L1 was found for Cancermelanoma and NSCLC , respectively , with no significant difference for genitourinary cancer .
26086854
A significant difference in activity of 22.8 % and 8.7 % according to PD-L1 was found for melanoma and NSCLC , respectively , with no significant difference for Cancergenitourinary cancer .
26086854
CONCLUSION : Overall , the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on Cancertumor cells .
26086854
The predictive value of PD-L1 on Cancertumor cells seems to be more robust for anti-PD-1 antibody ( nivolumab and pembrolizumab ) , and in the context of advanced melanoma and NSCLC .
26086854
The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody ( nivolumab and pembrolizumab ) , and in the context of Canceradvanced melanoma and NSCLC .
26096845
We report that Cancerrecurrent ovarian carcinomas after paclitaxel and carboplatin treatment have higher levels of spleen tyrosine kinase ( SYK ) and phospho-SYK .
26096845
Invitro , paclitaxel resistant cells expressed higher SYK , and the ratio of phospho-SYK and SYK positively associated with paclitaxel resistance in Cancerovarian cancer cells .
26096845
Analysis of the phosphotyrosine proteome in Cancerpaclitaxel resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule associated proteins .
26096845
Inhibition of SYK enhanced microtubule stability in Cancerpaclitaxel resistant tumor cells that were otherwise insensitive .
26108461
BACKGROUND : A rare nonconservative substitution ( G84E ) in the HOXB13 gene has been shown to be associated with AdverseOutcomerisk of prostate cancer .
26108461
BACKGROUND : A rare nonconservative substitution ( G84E ) in the HOXB13 gene has been shown to be associated with risk of Cancerprostate cancer .
26108461
DNA samples from male patients included in the Mayo Clinic Biobank ( MCB ) were genotyped to determine the frequency of the G84E mutation and its association with Cancervarious cancers .
26108461
In addition to donating a blood specimen , all MCB participants completed a baseline questionnaire to collect information on medical history and family history of Cancercancer .
26108461
Thirty-one percent ( n = 2,595 ) of participants had been diagnosed with Cancercancer , including 51.1 % of G84E carriers compared with just 30.6 % of noncarriers ( P = 0.004 ) .
26108461
G84E was most frequently observed among men with Cancerprostate cancer compared with men without cancer ( P < 0.0001 ) .
26108461
G84E was most frequently observed among men with prostate cancer compared with men without Cancercancer ( P < 0.0001 ) .
26108461
However , the mutation was also more commonly observed in men with Cancerbladder cancer ( P = 0.06 ) and leukemia ( P = 0.01 ) .
26108461
However , the mutation was also more commonly observed in men with bladder cancer ( P = 0.06 ) and Cancerleukemia ( P = 0.01 ) .
26108461
G84E carriers were more likely to have a positive family history of Cancerprostate cancer in a first-degree relative compared to noncarriers ( 36.2 % vs. 16.0 % , P = 0.0003 ) .
26108461
CONCLUSIONS : Our study confirms the association between the HOXB13 G84E variant and Cancerprostate cancer and suggests a novel association between G84E and leukemia and a suggestive association with bladder cancer .
26108461
CONCLUSIONS : Our study confirms the association between the HOXB13 G84E variant and prostate cancer and suggests a novel association between G84E and Cancerleukemia and a suggestive association with bladder cancer .
26108461
CONCLUSIONS : Our study confirms the association between the HOXB13 G84E variant and prostate cancer and suggests a novel association between G84E and leukemia and a suggestive association with Cancerbladder cancer .
26108461
Future investigation is warranted to confirm these associations in order to improve our understanding of the role of germline HOXB13 mutations in Cancerhuman cancer .
26108461
IMPACT : The associations between HOXB13 and prostate , Cancerleukemia , and bladder suggest that this gene is important in carcinogenesis .
26115874
BACKGROUND : Since head and Cancerneck cancer is characterized by poor survival rates , there is a demand for novel therapeutic targets and prognostic biomarkers .
26115874
However , their prognostic role in head and Cancerneck cancer remains unclear .
26115874
OBJECTIVE : To systematically review current evidence on the prognostic value of FGFR family members in head and Cancerneck squamous cell carcinoma ( HNSCC ) .
26115874
Relevant studies were assessed on AdverseOutcomerisk of bias using the Quality in Prognostic Studies ( QUIPS ) tool .
26115874
FGFR1 protein expression by Cancercancer associated fibroblasts correlated with poor survival outcome in one study ( p < 0.01 ) .
26115874
LIMITATIONS : AdverseOutcomeSignificant risk of bias has been identified among included studies .
26115874
CONCLUSION : In conclusion , evidence was found for prognostic value of FGFR1 expression in Cancercancer associated fibroblasts in HNSCC .
26124334
AIM : CancerNon small cell lung cancer ( NSCLC ) with minor mutations in the epidermal growth factor receptor ( EGFR ) gene , except for the common 15 base-pair deletions in exon 19 and the L858R mutation in exon 21 , is rare , and only few data exist on this patient population .
26124334
The response rate to TKI treatment was 29.5 % , and the Diseasedisease control rate was 63.6 % .
26124496
To identify genes that may predict response to ruxolitinib , we performed targeted next generation sequencing ( NGS ) of a panel of 28 genes recurrently mutated in Cancerhematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study .
26125448
BACKGROUND : Selumetinib ( AZD6244 , ARRY-142886 ) + docetaxel increases median overall survival ( OS ) and significantly improves progression-free survival ( PFS ) and objective response rate ( ORR ) compared with docetaxel alone in patients with KRAS mutant , Cancerstage IIIB/IV non-small-cell lung cancer ( NSCLC ; NCT00890825 ) .
26125448
METHODS : Retrospective analysis of OS , PFS , ORR and change in Cancertumour size at week 6 for different sub-populations of KRAS codon mutations .
26130666
PURPOSE : The incidence of Cancergastrointestinal stromal tumors ( GISTs ) harboring platelet derived growth factor receptor alpha ( PDGFRA ) mutations is low , therefore further investigation of the efficacy of imatinib in this subgroup was needed .
26130666
MATERIALS AND METHODS : Patients with PDGFRA-mutant GISTs who received imatinib as primary therapy for Diseaseadvanced disease between January 2000 and June 2012 were identified from the GIST registry of Asan Medical Center , Seoul , Korea .
26137564
METHODS : HERALD ( NCT02134015 ) was a double-blind , phase 2 study in patients with Cancernon small cell lung cancer ( NSCLC ) randomized to erlotinib with placebo or with high or low doses of patritumab , a monoclonal antibody targeted against human epidermal growth factor receptor 3 ( HER3 ) .
26137564
However , only 102 of the 215 randomized patients ( 47.4 % ) had Cancersufficient tumor samples for HRG mRNA measurement .
26137564
However , limitations of this analysis include the incomplete collection of Canceradequate tumor tissue and a lack of stratification .
26152787
Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of Cancercolorectal cancer ( CRC ) and has been identified as an independent predictor of disease progression and worse survival .
26152787
Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer ( CRC ) and has been identified as an independent predictor of Diseasedisease progression and worse survival .
26152787
Although mutations in the NOTCH1 receptor have not been described in CRC , we have previously discovered a NOTCH1 gene copy number gain in a portion of CancerCRC tumor samples .
26152787
In our CRC patient derived Cancertumor xenograft ( PDTX ) model , tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor , JAG1 ligand and cleaved Notch1 activity .
26152787
In our CRC patient derived tumor xenograft ( PDTX ) model , Cancertumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor , JAG1 ligand and cleaved Notch1 activity .
26162296
ERCC1 has been proposed as a prognostic and predictive biomarker for patients with Cancerurothelial carcinoma of the bladder but there are limited data on patients after radical cystectomy .
26162296
Associations with disease-free and Cancercancer specific survival , and the effect of adjuvant cisplatin based chemotherapy were assessed .
26162296
Further , ERCC1 mRNA expression and invitro sensitivity to cisplatin were correlated in 25 Cancerbladder urothelial carcinoma cell lines .
26162296
RESULTS : ERCC1 was expressed in 308 Cancertumors ( 71.3 % ) .
26162296
On multivariable analyses patients with CancerERCC1 positive tumors had significantly better disease-free survival ( HR 0.70 , p = 0.028 ) and cancer specific survival ( HR 0.70 , p = 0.032 ) than those with ERCC1 negative tumors .
26162296
On multivariable analyses patients with ERCC1 positive tumors had significantly better disease-free survival ( HR 0.70 , p = 0.028 ) and Cancercancer specific survival ( HR 0.70 , p = 0.032 ) than those with ERCC1 negative tumors .
26162296
On multivariable analyses patients with ERCC1 positive tumors had significantly better disease-free survival ( HR 0.70 , p = 0.028 ) and cancer specific survival ( HR 0.70 , p = 0.032 ) than those with CancerERCC1 negative tumors .
26162296
CONCLUSIONS : ERCC1 may be a prognostic biomarker for Cancerurothelial carcinoma ofthe bladder .
26162296
Patients with CancerERCC1 positive tumors may have better survival than those with ERCC1 negative tumors .
26162296
Patients with ERCC1 positive tumors may have better survival than those with CancerERCC1 negative tumors .
26167872
The CEBPA gene is mutated in 9 % of patients with Canceracute myeloid leukemia ( AML ) .
26167872
We show that C/EBPalpha p30 , but not the normal p42 isoform , preferentially interacts with Wdr5 , a key component of SET and MLL ( SET-domain and Cancermixed-lineage leukemia ) histone-methyltransferase complexes .
26169613
PURPOSE : Two phase II studies assessed the efficacy of vismodegib , a sonic hedgehog ( SHH ) pathway inhibitor that binds smoothened ( SMO ) , in pediatric and Canceradult recurrent medulloblastoma ( MB ) .
26169613
Progression-free survival ( PFS ) was longer in those with SHH-MB than in those with non-SHH-MB , and Diseaseprolonged disease stabilization occurred in 41 % of patient cases of SHH-MB .
26169613
Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the Cancertumor .
26179511
PURPOSE : A low mutation rate seems to be a general feature of Cancerpediatric cancers , in particular in oncofusion gene driven tumors .
26179511
PURPOSE : A low mutation rate seems to be a general feature of pediatric cancers , in particular in oncofusion gene driven Cancertumors .
26179511
Genetically , CancerEwing sarcoma is defined by balanced chromosomal EWS and ETS translocations , which give rise to oncogenic chimeric proteins ( EWS-ETS ) .
26179511
Other contributing somatic mutations involved in Diseasedisease development have only been observed at low frequency .
26179511
EXPERIMENTAL DESIGN : CancerTumor samples of 116 Ewing sarcoma patients were analyzed here .
26179511
EXPERIMENTAL DESIGN : Tumor samples of 116 CancerEwing sarcoma patients were analyzed here .
26179511
Whole-exome sequencing was performed on 50 CancerEwing sarcoma and 22 matched normal tissues .
26179511
A discovery dataset of 14 of these Cancertumor and normal pairs identified 232 somatic mutations .
26179511
Transcriptome analysis was performed in a subset of 14 of 50 CancerEwing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 Ewing sarcomas .
26179511
Transcriptome analysis was performed in a subset of 14 of 50 Ewing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 CancerEwing sarcomas .
26179511
RESULTS : CancerRelapsed tumors consistently showed a 2- to 3-fold increased number of mutations .
26179511
An oncogenic fibroblast growth factor receptor 1 ( FGFR1 ) mutation ( N546K ) was detected , and the FGFR1 locus frequently showed copy number gain ( 31.7 % ) in Cancerprimary tumors .
26179511
Furthermore , high-level FGFR1 expression was noted as a characteristic feature of CancerEwing sarcoma .
26179511
RNA interference of FGFR1 expression in CancerEwing sarcoma lines blocked proliferation and completely suppressed xenograft tumor growth .
26179511
RNA interference of FGFR1 expression in Ewing sarcoma lines blocked proliferation and completely suppressed Cancerxenograft tumor growth .
26179511
FGFR1 tyrosine kinase inhibitor ( TKI ) therapy in a patient with CancerEwing sarcoma relapse significantly reduced 18-FDG-PET activity .
26179511
CONCLUSIONS : FGFR1 may constitute a promising target for novel therapeutic approaches in CancerEwing sarcoma .
26181029
IMPORTANCE : Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors in unselected patients with head and Cancerneck squamous cell carcinoma ( HNSCC ) .
26181029
DESIGN , SETTING , AND PARTICIPANTS : Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial ( patients scheduled to undergo Cancerprimary cancer surgery are treated briefly with an investigational agent ) .
26181029
Whole-exome sequencing of Cancerpretreatment tumor and germline patient samples was performed at a quaternary care academic medical center , and a candidate somatic variant was experimentally investigated for mediating erlotinib response .
26181029
MAIN OUTCOMES AND MEASURES : Identification of Cancerpretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib .
26181029
Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the Cancerpatient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants .
26181029
Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of Cancertumor somatic variants .
26181029
RESULTS : No EGFR alterations were observed in the Cancerpretreatment tumor DNA .
26181029
Paradoxically , the Cancertumor harbored an activating MAPK1 E322K mutation ( allelic fraction 0.13 ) , which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer .
26181029
Paradoxically , the tumor harbored an activating MAPK1 E322K mutation ( allelic fraction 0.13 ) , which predicts ERK activation and erlotinib resistance in CancerEGFR-mutant lung cancer .
26181354
Author information : ( 1 ) Thoracic Oncology Service , Division of CancerSolid Tumor Oncology , Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , New York2Department of Medicine , Weill Cornell Medical College , New York , New York .
26182309
IMPORTANCE : The Bruton tyrosine kinase ( BTK ) inhibitor ibrutinib is effective in patients with Cancerchronic lymphocytic leukemia ( CLL ) .
26182309
For patients who discontinued therapy because of Diseasedisease progression , targeted deep sequencing was performed in samples at baseline and time of relapse .
26182309
RESULTS : With a median follow-up of 20 months , 232 patients remained on therapy , 31 had discontinued because of Diseasedisease progression , and 45 had discontinued for other reasons .
26182309
DiseaseDisease progression includes Richter 's transformation ( RT ) or progressive CLL .
26182309
Outcomes data show AdverseOutcomepoor prognosis after discontinuation , especially for those patients with RT. .
26204491
CCNE1 gene amplification is present in 15-20 Cancer% ovary tumor specimens .
26204491
Here , we showed that Cyclin E1 ( CCNE1 ) was overexpressed in 30 % of Cancerestablished ovarian cancer cell lines .
26204491
We also showed that CCNE1 was stained positive in over 40 % of Cancerprimary ovary tumor specimens regardless of their histological types while CCNE1 staining was either negative or low in normal ovary and benign ovary tumor tissues .
26204491
We also showed that CCNE1 was stained positive in over 40 % of primary ovary tumor specimens regardless of their histological types while CCNE1 staining was either negative or low in normal ovary and Cancerbenign ovary tumor tissues .
26204491
However , the status of CCNE1 overexpression was not associated with the tumorigenic potential of Cancerovarian cancer cell lines and also did not correlate with pathological grades of ovary tumor specimens .
26204491
However , the status of CCNE1 overexpression was not associated with the tumorigenic potential of ovarian cancer cell lines and also did not correlate with pathological grades of Cancerovary tumor specimens .
26204491
CancerOvarian cancer cells with elevated CCNE1 expression were 40 times more sensitive to Cdk2 inhibitorSNS-032 than those without inherent CCNE1 overexpression .
26204491
Moreover , SNS-032 greatly prolonged the survival of mice bearing Cancerovary tumors with inherent CCNE1 overexpression .
26204491
This study suggests that Cancerovary tumors with elevated CCNE1 expression may be staged for Cdk2 targeted therapy .
26207647
OBJECTIVE : This study explored the level and clinical significance of serum Gas6 in patients with Canceroral squamous cell carcinoma ( OSCC ) .
26207647
OSCC patients with late TNM stage ( III , IV ) had a relatively high serum Gas6 concentration compared with those with early stage ( I , II ) ( P < 0.01 ) and patients with poorly differentiated Cancertumors had a higher level of serum Gas6 than those with well differentiated tumors ( P < 0.01 ) .
26207647
OSCC patients with late TNM stage ( III , IV ) had a relatively high serum Gas6 concentration compared with those with early stage ( I , II ) ( P < 0.01 ) and patients with poorly differentiated tumors had a higher level of serum Gas6 than those with well differentiated Cancertumors ( P < 0.01 ) .
26207647
Multivariate logistic regression analysis demonstrated that high serum Gas6 was an AdverseOutcomeindependent risk factor for lymph nodal metastases in OSCC patients ( OR = 2.79 , 95 % CI : 1.72-4 .48 ) .
26216294
Oncogenic TRK fusions induce Cancercancer cell proliferation and engage critical cancer related downstream signaling pathways .
26216294
Oncogenic TRK fusions induce cancer cell proliferation and engage Cancercritical cancer related downstream signaling pathways .
26216294
These TRK fusions occur rarely , but in a diverse spectrum of Cancertumor histologies .
26216294
Preclinical models of LOXO-101 using TRK-fusion-bearing human derived Cancercancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro , and tumor growth in vivo .
26216294
Preclinical models of LOXO-101 using TRK-fusion-bearing human derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro , and Cancertumor growth in vivo .
26216294
The Cancertumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay .
26216294
The tumor of a 41-year-old woman with Cancersoft-tissue sarcoma metastatic to the lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay .
26216294
NCT02122913 ) , this patient 's Cancertumors underwent rapid and substantial tumor regression , with an accompanying improvement in pulmonary dyspnea , oxygen saturation , and plasma tumor markers.SIGNIFICANCE : TRK fusions have been deemed putative oncogenic drivers , but their clinical significance remained unclear .
26216294
NCT02122913 ) , this patient 's tumors underwent rapid and Cancersubstantial tumor regression , with an accompanying improvement in pulmonary dyspnea , oxygen saturation , and plasma tumor markers.SIGNIFICANCE : TRK fusions have been deemed putative oncogenic drivers , but their clinical significance remained unclear .
26216294
NCT02122913 ) , this patient 's tumors underwent rapid and substantial tumor regression , with an accompanying improvement in pulmonary dyspnea , oxygen saturation , and Cancerplasma tumor markers.SIGNIFICANCE : TRK fusions have been deemed putative oncogenic drivers , but their clinical significance remained unclear .
26216294
A patient with a Cancermetastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel , highly selective TRK inhibitor , LOXO-101 , providing the first clinical evidence of benefit from inhibiting TRK fusions .
26216294
A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and Cancersubstantial tumor regression with a novel , highly selective TRK inhibitor , LOXO-101 , providing the first clinical evidence of benefit from inhibiting TRK fusions .
26221234
CancerAnaplastic lymphoma kinase ( ALK )-positive diffuse large B-cell lymphoma ( ALK + DLBCL ) is a rare and poorly characterized subtype of lymphoma .
26221234
Anaplastic lymphoma kinase ( CancerALK )-positive diffuse large B-cell lymphoma ( ALK + DLBCL ) is a rare and poorly characterized subtype of lymphoma .
26221234
Anaplastic lymphoma kinase ( ALK )-positive diffuse large B-cell lymphoma ( ALK + DLBCL ) is a rare and poorly characterized subtype of Cancerlymphoma .
26221234
Reports suggest that this type of Cancertumor responds poorly to standard regimens for non Hodgkin 's lymphoma , with rituximab playing no therapeutic role due to the absence of CD20 expression .
26221234
Reports suggest that this type of tumor responds poorly to standard regimens for non Hodgkin 's Cancerlymphoma , with rituximab playing no therapeutic role due to the absence of CD20 expression .
26221234
In view of the expression of ALK in this Diseasedisease , it is plausible that the ALK inhibitor crizotinib may be an effective treatment .
26221234
He refused to accept an autologous stem-cell transplantation , after which the Diseasedisease progressed rapidly .
26221234
His symptoms alleviated for a short time but soon worsened and the patient died of Diseasemassive progressive disease .
26243863
The CancerCancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7 % of patients with colorectal cancer .
26243863
The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7 % of patients with Cancercolorectal cancer .
26243863
Introduction of these HER2 activating mutations into Cancercolorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation .
26243863
HER2 gene sequencing of 48 cetuximab resistant , quadruple ( KRAS , NRAS , BRAF , and PIK3CA ) wild-type ( WT ) Cancercolorectal cancer patient derived xenografts ( PDX ) identified 4 PDXs with HER2 mutations .
26243863
Treatment with a single HER2 targeted drug ( trastuzumab , neratinib , or lapatinib ) delayed Cancertumor growth , but dual HER2 targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2 mutated PDXs.SIGNIFICANCE : HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines , and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2 targeted therapy .
26243863
Treatment with a single HER2 targeted drug ( trastuzumab , neratinib , or lapatinib ) delayed tumor growth , but dual HER2 targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2 mutated PDXs.SIGNIFICANCE : HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines , and PDXs with HER2 mutations show Cancerdurable tumor regression when treated with dual HER2 targeted therapy .
26243863
These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in Cancermetastatic colorectal cancer .
26255196
The introduction of trastuzumab as adjuvant treatment for patients with CancerHER2 positive breast cancer changed the natural course of early-stage disease .
26255196
The introduction of trastuzumab as adjuvant treatment for patients with HER2 positive breast cancer changed the natural course of Diseaseearly-stage disease .
26255196
Of note , evidence supports the use of lighter chemotherapy regimens with one year of adjuvant trastuzumab as backbone , for women with Cancersmall HER2 positive breast tumors , where the omission of anthracyclines did not compromise the clinical outcome .
26255196
Despite the successes achieved so far , a proportion of women with Cancerearly-stage HER2 positive breast cancer , will still experience disease recurrence .
26255196
Despite the successes achieved so far , a proportion of women with early-stage HER2 positive breast cancer , will still experience Diseasedisease recurrence .
26255196
Similarly , inconsistent results have been reported for the predictive ability of alterations affecting the PI3K signaling pathway or the quantification of Cancertumor infiltrating lymphocytes .
26255196
In the era of personalized oncology , rigorous translational and clinical collaborative efforts are needed to further advance the field of treatment of patients with CancerHER2 positive breast cancer .
26256760
BACKGROUND : CancerFollicular lymphoma is a clinically and genetically heterogeneous disease , but the prognostic value of somatic mutations has not been systematically assessed .
26256760
BACKGROUND : Follicular lymphoma is a clinically and genetically Diseaseheterogeneous disease , but the prognostic value of somatic mutations has not been systematically assessed .
26256760
We aimed to improve AdverseOutcomerisk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model .
26256760
METHODS : We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 Cancerfollicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ( R-CHOP ) .
26256760
Eligible patients had symptomatic , Canceradvanced stage follicular lymphoma and were previously untreated .
26256760
Mutations and clinical factors were incorporated into a AdverseOutcomerisk model for failure-free survival using multivariable L1 penalised Cox regression .
26256760
We validated the AdverseOutcomerisk model in an independent population based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation .
26256760
We validated the risk model in an independent population based cohort of 107 patients with Cancersymptomatic follicular lymphoma considered ineligible for curative irradiation .
26256760
FINDINGS : We established a AdverseOutcomeclinicogenetic risk model ( termed m7-FLIPI ) that included the mutation status of seven genes ( EZH2 , ARID1A , MEF2B , EP300 , FOXO1 , CREBBP , and CARD11 ) , the Follicular Lymphoma International Prognostic Index ( FLIPI ) , and Eastern Cooperative Oncology Group ( ECOG ) performance status .
26256760
In the validation cohort , AdverseOutcomerisk stratification by m7-FLIPI outperformed FLIPI alone ( HR 2.18 , 95 % CI 1.21-3 .92 ) , and FLIPI combined with ECOG performance status ( HR 2.03 , 95 % CI 1.12-3 .67 ) .
26256760
INTERPRETATION : Integration of the mutational status of seven genes with AdverseOutcomeclinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure .
26256760
INTERPRETATION : Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with Cancerfollicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure .
26256760
INTERPRETATION : Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest AdverseOutcomerisk of treatment failure .
26261420
This study tested the potential of circulating RNA based signals as predictive biomarkers for docetaxel response in patients with Cancermetastatic castration resistant prostate cancer ( CRPC ) .
26267899
BACKGROUND : Protein tyrosine phosphatase receptor type D ( PTPRD ) is a putative tumor suppressor in Cancerseveral cancers including head and neck squamous cell carcinoma ( HNSCC ) .
26267899
BACKGROUND : Protein tyrosine phosphatase receptor type D ( PTPRD ) is a putative tumor suppressor in several cancers including head and Cancerneck squamous cell carcinoma ( HNSCC ) .
26267899
METHODS : We analyzed data from The CancerCancer Genome Atlas ( TCGA ) and our previous whole-exome sequencing study and summarized the mutation , methylation , and copy number status of PTPRD in HNSCC and other cancers .
26267899
METHODS : We analyzed data from The Cancer Genome Atlas ( TCGA ) and our previous whole-exome sequencing study and summarized the mutation , methylation , and copy number status of PTPRD in HNSCC and Cancerother cancers .
26268241
CancerAngioimmunoblastic T-cell lymphoma ( AITL ) is a common subtype of peripheral T-cell lymphoma ( PTCL ) with a poor prognosis .
26268241
Angioimmunoblastic T-cell lymphoma ( AITL ) is a common subtype of Cancerperipheral T-cell lymphoma ( PTCL ) with a poor prognosis .
26268241
Angioimmunoblastic T-cell lymphoma ( AITL ) is a common subtype of peripheral T-cell lymphoma ( PTCL ) with a AdverseOutcomepoor prognosis .
26269204
However , despite Cancerimpressive tumor responses in T790M positive patients , acquired resistance to this drug limits the benefit of this compound .
26287849
BACKGROUND : BRAF V600 mutations occur in Cancervarious nonmelanoma cancers .
26287849
We undertook a histology independent phase 2 " basket " study of vemurafenib in CancerBRAF V600 mutation positive nonmelanoma cancers .
26287849
METHODS : We enrolled patients in six prespecified Cancercancer cohorts ; patients with all other tumor types were enrolled in a seventh cohort .
26287849
METHODS : We enrolled patients in six prespecified cancer cohorts ; patients with all Cancerother tumor types were enrolled in a seventh cohort .
26287849
A total of 122 patients with CancerBRAF V600 mutation positive cancer were treated , including 27 patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
A total of 122 patients with BRAF V600 mutation positive cancer were treated , including 27 patients with Cancercolorectal cancer who received vemurafenib and cetuximab .
26287849
RESULTS : In the cohort with Cancernon-small-cell lung cancer , the response rate was 42 % ( 95 % confidence interval [ CI ] , 20 to 67 ) and median progression-free survival was 7.3 months ( 95 % CI , 3.5 to 10.8 ) .
26287849
In the cohort with DiseaseErdheim-Chester disease or Langerhans '-cell histiocytosis , the response rate was 43 % ( 95 % CI , 18 to 71 ) ; the median treatment duration was 5.9 months ( range , 0.6 to 18.6 ) , and no patients had disease progression during therapy .
26287849
In the cohort with Erdheim-Chester disease or Langerhans '-cell histiocytosis , the response rate was 43 % ( 95 % CI , 18 to 71 ) ; the median treatment duration was 5.9 months ( range , 0.6 to 18.6 ) , and no patients had Diseasedisease progression during therapy .
26287849
There were anecdotal responses among patients with Cancerpleomorphic xanthoastrocytoma , anaplastic thyroid cancer , cholangiocarcinoma , salivary-duct cancer , ovarian cancer , and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , Canceranaplastic thyroid cancer , cholangiocarcinoma , salivary-duct cancer , ovarian cancer , and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , anaplastic thyroid cancer , Cancercholangiocarcinoma , salivary-duct cancer , ovarian cancer , and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , anaplastic thyroid cancer , cholangiocarcinoma , Cancersalivary-duct cancer , ovarian cancer , and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , anaplastic thyroid cancer , cholangiocarcinoma , salivary-duct cancer , Cancerovarian cancer , and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , anaplastic thyroid cancer , cholangiocarcinoma , salivary-duct cancer , ovarian cancer , and Cancerclear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
26287849
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , anaplastic thyroid cancer , cholangiocarcinoma , salivary-duct cancer , ovarian cancer , and clear-cell sarcoma and among patients with Cancercolorectal cancer who received vemurafenib and cetuximab .
26287849
Safety was similar to that in prior studies of vemurafenib for Cancermelanoma .
26287849
CONCLUSIONS : BRAF V600 appears to be a targetable oncogene in some , but not all , Cancernonmelanoma cancers .
26287849
Preliminary vemurafenib activity was observed in Cancernon-small-cell lung cancer and in Erdheim-Chester disease and Langerhans '-cell histiocytosis .
26287849
Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in DiseaseErdheim-Chester disease and Langerhans '-cell histiocytosis .
26287849
The histologic context is an important determinant of response in BRAF V600 mutated Cancercancers .
26291055
BACKGROUND : Despite good initial response to chemotherapy , 30 % of Ewing 's Cancersarcoma ( EWS ) patients with localised tumours develop recurrent disease , associated with poor prognosis .
26291055
BACKGROUND : Despite good initial response to chemotherapy , 30 % of Ewing 's sarcoma ( EWS ) patients with Cancerlocalised tumours develop recurrent disease , associated with poor prognosis .
26291055
BACKGROUND : Despite good initial response to chemotherapy , 30 % of Ewing 's sarcoma ( EWS ) patients with localised tumours develop Diseaserecurrent disease , associated with poor prognosis .
26291055
BACKGROUND : Despite good initial response to chemotherapy , 30 % of Ewing 's sarcoma ( EWS ) patients with localised tumours develop recurrent disease , associated with AdverseOutcomepoor prognosis .
26291055
METHODS : Cell viability assays , drug dose responses , immunoblots , rescue with gene transfer , Cancermice tumour models , and statistical comparisons of tumour growth and Kaplan-Meier survival curves .
26291055
METHODS : Cell viability assays , drug dose responses , immunoblots , rescue with gene transfer , mice tumour models , and statistical comparisons of Cancertumour growth and Kaplan-Meier survival curves .
26304929
Activating mutations in EZH2 are found in a subset of Cancermelanoma that contributes to disease progression by inactivating tumor suppressor genes .
26304929
Activating mutations in EZH2 are found in a subset of melanoma that contributes to Diseasedisease progression by inactivating tumor suppressor genes .
26304929
We show that inhibition of EZH2 has potent effects on the growth of both wild-type and CancerEZH2 mutant human melanoma in vitro particularly in cell lines harboring the EZH2Y646 activating mutation .
26304929
These results emphasize a critical role for EZH2 in the proliferation and viability of Cancermelanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with melanoma .
26304929
These results emphasize a critical role for EZH2 in the proliferation and viability of melanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with Cancermelanoma .
26307133
PURPOSE : Copy number alterations have been shown to be involved in Cancermelanoma pathogenesis .
26307133
The randomized phase III clinical trial E2603 : carboplatin , paclitaxel , +/- sorafenib ( CP vs. CPS ) offers a large collection of Cancertumor samples to evaluate association of somatic mutations , genomic alterations , and clinical outcomes , prior to current FDA approved therapies .
26307133
RESULTS : CPS therapy was associated with improved progression-free survival ( PFS ) compared with CP in patients with Cancertumors with RAF1 ( cRAF ) gene copy gains ( HR , 0.372 ; P = 0.025 ) or CCND1 gene copy gains ( HR , 0.45 ; P = 0.035 ) .
26307133
CPS therapy was associated with improved overall survival ( OS ) compared with CP in patients with Cancertumors with KRAS gene copy gains ( HR , 0.25 ; P = 0.035 ) .
26307133
BRAF gene copy gain and MET amplification were more common in samples with V600K versus V600E mutations ( P < 0.001 ) , which was validated in The CancerCancer Genome Atlas ( TCGA ) dataset .
26307133
CONCLUSIONS : We observed improved treatment response with CPS in patients with Cancermelanoma whose tumors have RAF1 ( cRAF ) , KRAS , or CCND1 amplification , all of which can be attributed to sorafenib targeting CRAF .
26307133
CONCLUSIONS : We observed improved treatment response with CPS in patients with melanoma whose Cancertumors have RAF1 ( cRAF ) , KRAS , or CCND1 amplification , all of which can be attributed to sorafenib targeting CRAF .
26309414
BACKGROUND : We analyzed the expression of heme oxygenase-1 ( HO-1 ) in patients undergoing radical nephrectomy for Canceradvanced clear cell renal cell carcinoma ( CC-RCC ) and evaluated the effects of the targeted therapies treated with sorafenib and sunitinib .
26309414
METHODS : Expression of HO-1 in Cancercancer tissue from 66 patients was measured by immunohis-tochemical staining .
26309414
The patients received either oral sorafenib ( n = 40 ) or oral sunitinib ( n = 26 ) within 4 weeks after nephrectomy and were followed up long term to determine the Cancertumor response and prognosis .
26309414
In the low HO-1 level group , a Cancerhigher tumor response rate and a longer survival time was achieved in patients who received sorafenib or sunitinib .
26309414
Multivariate analysis showed that HO-1 expression was an independent prognostic factor for Cancertumor response and overall survival .
26309414
CONCLUSION : High expression of HO-1 was associated with a Cancerlower tumor response rate and a shorter overall survival time when compared with low expression of HO-1 .
26311741
Sphingosine kinase 1 ( SPHK1 ) , an oncogenic kinase , has previously been found to be upregulated in various types of Cancerhuman malignancy and to play a crucial role in tumor development and progression .
26311741
Sphingosine kinase 1 ( SPHK1 ) , an oncogenic kinase , has previously been found to be upregulated in various types of human malignancy and to play a crucial role in Cancertumor development and progression .
26311741
Although SPHK1 has gained increasing prominence as an important enzyme in Cancercancer biology , its potential as a predictive biomarker and a therapeutic target in cervical cancer remains unknown .
26311741
Although SPHK1 has gained increasing prominence as an important enzyme in cancer biology , its potential as a predictive biomarker and a therapeutic target in Cancercervical cancer remains unknown .
26311741
SPHK1 expression was examined in 287 formalin fixed , Cancerparaffin embedded cervical cancer tissues using immunohistochemistry , and its clinical implications and prognostic significance were analyzed .
26311741
CancerCervical cancer cell lines including HeLa and SiHa were treated with the SPHK inhibitors SKI-II or FTY720 , and effects on cell survival , apoptosis , angiogenesis , and invasion were examined .
26311741
Moreover , the effects of FTY720 on Cancertumor growth were evaluated using a patient derived xenograft ( PDX ) model of cervical cancer .
26311741
Moreover , the effects of FTY720 on tumor growth were evaluated using a patient derived xenograft ( PDX ) model of Cancercervical cancer .
26311741
Immunohistochemical analysis revealed that expression of SPHK1 was significantly increased in Cancercervical cancer compared with normal tissues .
26311741
SPHK1 expression was significantly associated with Cancertumor size , invasion depth , FIGO stage , lymph node metastasis , and lymphovascular invasion .
26311741
SPHK1 expression was significantly associated with tumor size , invasion depth , FIGO stage , Cancerlymph node metastasis , and lymphovascular invasion .
26311741
Treatment with SPHK inhibitors significantly reduced viability and increased apoptosis in Cancercervical cancer cells .
26311741
Furthermore , FTY720 significantly decreased in vivo Cancertumor weight in the PDX model of cervical cancer .
26311741
Furthermore , FTY720 significantly decreased in vivo tumor weight in the PDX model of Cancercervical cancer .
26311741
We provide the first convincing evidence that SPHK1 is involved in Cancertumor development and progression of cervical cancer .
26311741
We provide the first convincing evidence that SPHK1 is involved in tumor development and progression of Cancercervical cancer .
26311741
Our data suggest that SPHK1 might be a potential prognostic marker and therapeutic target for the treatment of Cancercervical cancer .
26313362
BACKGROUND : Immunotherapy can become a crucial therapeutic option to improve prognosis for Cancerlung cancer patients .
26313362
First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ligand PD-L1 have shown promising results in Cancerseveral solid tumors .
26313362
However , in Cancerlung cancer the diagnostic , prognostic and predictive value of these immunologic factors remains unclear .
26313362
METHOD : The impact of both factors was evaluated in a study collective of 321 clinically well annotated patients with Cancernon small lung cancer ( NSCLC ) using immunohistochemistry .
26313362
RESULTS : PD-1 expression by Cancertumor infiltrating lymphocytes ( TILs ) was found in 22 % , whereas tumor cell associated PD-L1 expression was observed in 24 % of the NSCLC tumors .
26313362
RESULTS : PD-1 expression by tumor infiltrating lymphocytes ( TILs ) was found in 22 % , whereas Cancertumor cell associated PD-L1 expression was observed in 24 % of the NSCLC tumors .
26313362
RESULTS : PD-1 expression by tumor infiltrating lymphocytes ( TILs ) was found in 22 % , whereas tumor cell associated PD-L1 expression was observed in 24 % of the CancerNSCLC tumors .
26313362
Interestingly , PD-L1 expression on Cancertumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas ( SCC , p = 0.042 , log rank test ) , with adjuvant therapy ( p = 0.017 ) , with increased tumor size ( pT2-4 , p = 0.039 ) and with positive lymph node status ( pN1-3 , p = 0.010 ) .
26313362
Interestingly , PD-L1 expression on tumor cells was associated with improved overall survival in Cancerpulmonary squamous cell carcinomas ( SCC , p = 0.042 , log rank test ) , with adjuvant therapy ( p = 0.017 ) , with increased tumor size ( pT2-4 , p = 0.039 ) and with positive lymph node status ( pN1-3 , p = 0.010 ) .
26313362
Interestingly , PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas ( SCC , p = 0.042 , log rank test ) , with adjuvant therapy ( p = 0.017 ) , with increased Cancertumor size ( pT2-4 , p = 0.039 ) and with positive lymph node status ( pN1-3 , p = 0.010 ) .
26313362
CONCLUSION : One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC , with increased Cancertumor size , with a positive lymph node status and NSCLC patients who received adjuvant therapies .
26313362
This study provides first data for immune-context AdverseOutcomerelated risk stratification of NSCLC patients .
26314551
Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in Cancermelanoma , BRAF gene fusions have not been investigated as anticancer drug targets .
26314551
In our study , a wide variety of Cancertumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne ( TM ) or FoundationOne Heme ( TM ) comprehensive genomic profiling assays .
26314551
In our study , a wide variety of tumors underwent comprehensive genomic profiling for hundreds of Cancerknown cancer genes using the FoundationOne ( TM ) or FoundationOne Heme ( TM ) comprehensive genomic profiling assays .
26314551
BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 ( 0.3 % ) of 20,573 Cancertumors , across 12 distinct tumor types , including 20 novel BRAF fusions .
26314551
BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 ( 0.3 % ) of 20,573 tumors , across 12 Cancerdistinct tumor types , including 20 novel BRAF fusions .
26314551
BRAF fusions included 3 % ( 14/531 ) of Cancermelanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of Cancergliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of Cancerthyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) Cancerpancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) Cancernonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of Cancercolorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. Cancernonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. CancernonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. Cancernonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) nonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. Cancernonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
26314551
In conclusion , BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms , but enriched in CancerSpitzoid melanoma , pilocytic astrocytomas , pancreatic acinar and papillary thyroid cancers .
26314551
In conclusion , BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms , but enriched in Spitzoid melanoma , Cancerpilocytic astrocytomas , pancreatic acinar and papillary thyroid cancers .
26314551
In conclusion , BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms , but enriched in Spitzoid melanoma , pilocytic astrocytomas , pancreatic acinar and Cancerpapillary thyroid cancers .
26324360
PURPOSE : No effective systemic therapy exists for patients with metastatic low-grade serous ( LGS ) Cancerovarian cancers .
26324360
BRAF and KRAS mutations are common in serous borderline ( SB ) and CancerLGS ovarian cancers , and MEK inhibition has been shown to induce tumor regression in a minority of patients ; however , no correlation has been observed between mutation status and clinical response .
26324360
BRAF and KRAS mutations are common in serous borderline ( SB ) and LGS ovarian cancers , and MEK inhibition has been shown to induce Cancertumor regression in a minority of patients ; however , no correlation has been observed between mutation status and clinical response .
26324360
PATIENTS AND METHODS : Next generation sequencing was used to analyze this patient 's Cancertumor as well as an additional 28 SB/LGS tumors .
26324360
PATIENTS AND METHODS : Next generation sequencing was used to analyze this patient 's tumor as well as an additional 28 CancerSB/LGS tumors .
26324360
RESULTS : Analysis of the extraordinary responder 's Cancertumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1 .
26324360
Functional characterization demonstrated that this mutant induced extracellular signal regulated kinase pathway activation , promoted anchorage independent growth and Cancertumor formation in mice , and retained sensitivity to selumetinib .
26324360
Analysis of Canceradditional LGS/SB tumors identified mutations predicted to induce extracellular signal regulated kinase pathway activation in 82 % ( 23 of 28 ) , including two patients with BRAF fusions , one of whom achieved an ongoing complete response to MEK inhibitor based combination therapy .
26324360
CONCLUSION : Alterations affecting the mitogen activated protein kinase pathway are present in the majority of patients with CancerLGS ovarian cancer .
26324360
These findings , coupled with the observation that a subset of patients with Cancerrecurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy , support additional clinical studies of MEK inhibitors in this disease .
26324360
These findings , coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy , support additional clinical studies of MEK inhibitors in this Diseasedisease .
26324363
PATIENTS AND METHODS : Eligible patients with Canceradvanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently ( 7 days on/7 days off ) .
26324363
The most common treatment-emergent adverse events included Diseasehyperphosphatemia ( 65 % ) , asthenia ( 55 % ) , dry mouth ( 45 % ) , nail toxicity ( 35 % ) , constipation ( 34 % ) , decreased appetite ( 32 % ) , and dysgeusia ( 31 % ) .
26324363
The most common treatment-emergent adverse events included hyperphosphatemia ( 65 % ) , Diseaseasthenia ( 55 % ) , dry mouth ( 45 % ) , nail toxicity ( 35 % ) , constipation ( 34 % ) , decreased appetite ( 32 % ) , and dysgeusia ( 31 % ) .
26324363
The most common treatment-emergent adverse events included hyperphosphatemia ( 65 % ) , asthenia ( 55 % ) , dry mouth ( 45 % ) , Diseasenail toxicity ( 35 % ) , constipation ( 34 % ) , decreased appetite ( 32 % ) , and dysgeusia ( 31 % ) .
26324363
Twenty-seven patients ( 42 % ) experienced grade > = 3 treatment-emergent adverse events , and one dose limiting Diseasetoxicity of grade 3 ALT elevation was observed at 12 mg daily .
26324363
Among 23 response-evaluable patients with Cancertumor FGFR pathway alterations , four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer ( all with FGFR2 or FGFR3 translocations ) ; 16 patients had stable disease .
26324363
Among 23 response-evaluable patients with tumor FGFR pathway alterations , four confirmed responses and one unconfirmed partial response were observed in patients with Cancerglioblastoma and urothelial and endometrial cancer ( all with FGFR2 or FGFR3 translocations ) ; 16 patients had stable disease .
26324363
Among 23 response-evaluable patients with tumor FGFR pathway alterations , four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and Cancerendometrial cancer ( all with FGFR2 or FGFR3 translocations ) ; 16 patients had stable disease .
26324363
Among 23 response-evaluable patients with tumor FGFR pathway alterations , four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer ( all with FGFR2 or FGFR3 translocations ) ; 16 patients had Diseasestable disease .
26338418
Individuals that harbor uORF1 have a marked resistance to platinum based agents , illustrated by the significantly reduced progression-free survival of Cancerpediatric ependymoma patients treated with such compounds .
26341751
A proliferative marker , expressed as the percentage of cells in a cell cycle , has been developed and used as a discriminant of more aggressive malignant phenotypes in Cancerearly breast cancer ( BC ) .
26341751
In CancerER+ tumors , the HR for high versus low Ki-67 was similar and significant ( HR = 1.51 , 95 % CI 1.25-1 .81 , P < 0.0001 ) .
26341751
The Ki-67 threshold with the greatest prognostic significance is as yet unknown , but a cut-off > 25 % is associated with a greater AdverseOutcomerisk of death compared with lower expression rates .
26351323
AKT1 ( E17K ) mutations occur at low frequency in a variety of Cancersolid tumors , including those of the breast and urinary bladder .
26351323
Moreover , the therapeutic potential of AKT inhibitors in Cancerhuman tumors with an endogenous AKT1 ( E17K ) mutation is not known .
26351323
Both AKT inhibitors caused highly significant growth inhibition of Cancerbreast cancer explant models with AKT1 ( E17K ) mutation .
26351323
Furthermore , in a phase I clinical study , the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and Cancerovarian cancer with tumors containing AKT1 ( E17K ) mutations .
26351323
Furthermore , in a phase I clinical study , the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with Cancertumors containing AKT1 ( E17K ) mutations .
26351323
In CancerMGH-U3 bladder cancer xenografts , which contain both AKT1 ( E17K ) and FGFR3 ( Y373C ) mutations , AZD5363 monotherapy did not significantly reduce tumor growth , but tumor regression was observed in combination with the FGFR inhibitor AZD4547 .
26351323
In MGH-U3 bladder cancer xenografts , which contain both AKT1 ( E17K ) and FGFR3 ( Y373C ) mutations , AZD5363 monotherapy did not significantly reduce Cancertumor growth , but tumor regression was observed in combination with the FGFR inhibitor AZD4547 .
26351323
In MGH-U3 bladder cancer xenografts , which contain both AKT1 ( E17K ) and FGFR3 ( Y373C ) mutations , AZD5363 monotherapy did not significantly reduce tumor growth , but Cancertumor regression was observed in combination with the FGFR inhibitor AZD4547 .
26351323
The data show that Cancertumors with AKT1 ( E17K ) mutations are rational therapeutic targets for AKT inhibitors , although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor .
26351323
The data show that tumors with AKT1 ( E17K ) mutations are rational therapeutic targets for AKT inhibitors , although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the Cancersame tumor .
26352686
BACKGROUND : BRAF V600E is the genetic lesion underlying Cancerhairy-cell leukemia .
26352686
We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with Cancerhairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues .
26352686
We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had Diseasedisease that was refractory to purine analogues .
26352686
Drug related adverse events were usually of grade 1 or 2 , and the events most frequently leading to dose reductions were rash and arthralgia or Diseasearthritis .
26352686
CancerSecondary cutaneous tumors ( treated with simple excision ) developed in 7 of 50 patients .
26352686
CONCLUSIONS : A short oral course of vemurafenib was highly effective in patients with relapsed or Cancerrefractory hairy-cell leukemia .
26359368
Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated Cancerthyroid cancer ( PDTC ) .
26359368
The 22q tumor suppressor NF2 , encoding merlin , is implicated in this interaction because of its frequent loss of function in Cancerhuman thyroid cancer cell lines .
26359368
The increased MAPK output generated by NF2 loss in CancerRAS-mutant cancers may inform therapeutic strategies , as it generates greater dependency on the MAPK pathway for viability.SIGNIFICANCE : Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation .
26359985
Clinically acquired resistance to MAPK inhibitor ( MAPKi ) therapies for Cancermelanoma can not be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity .
26359985
We sought to discover non genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative , transcriptomic-methylomic analysis of patient matched Cancermelanoma tumors biopsied before therapy and during disease progression .
26359985
We sought to discover non genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative , transcriptomic-methylomic analysis of patient matched melanoma tumors biopsied before therapy and during Diseasedisease progression .
26359985
Transcriptomic alterations across Cancerresistant tumors were highly recurrent , in contrast to mutations , and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites .
26359985
Transcriptomic alterations across resistant tumors were highly recurrent , in contrast to mutations , and were frequently correlated with differential methylation of Cancertumor cell-intrinsic CpG sites .
26359985
We identified in the Cancertumor cell compartment supra-physiologic c-MET up-expression , infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance .
26359985
Importantly , Diseasehigh intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency and exhaustion and loss of antigen presentation in half of disease-progressive melanomas , suggesting cross-resistance to salvage anti-PD-1 and PD-L1 immunotherapy .
26359985
Importantly , high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency and exhaustion and loss of antigen presentation in half of Cancerdisease-progressive melanomas , suggesting cross-resistance to salvage anti-PD-1 and PD-L1 immunotherapy .
26359985
Thus , Cancermelanoma acquires MAPKi resistance with highly dynamic and recurrent non genomic alterations and co-evolving intra-tumoral immunity .
26370156
We identified amplification of RICTOR , a key component of the mTOR complex 2 ( mTORC2 ) , as the sole actionable genomic alteration in an 18-year-old never-smoker with Cancerlung adenocarcinoma .
26370156
Amplification of RICTOR occurs in 13 % of Cancerlung cancers ( 1,016 cases ) in The Cancer Genome Atlas and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling .
26370156
Amplification of RICTOR occurs in 13 % of lung cancers ( 1,016 cases ) in The CancerCancer Genome Atlas and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling .
26370156
Its oncogenic roles were suggested by decreased Cancerlung cancer cell growth both in vitro and in vivo with RICTOR ablation , and the transforming capacity of RICTOR in a Ba/F3-cell system .
26370156
The mTORC1/2 inhibitors were significantly more active against RICTOR amplified Cancerlung cancer cells as compared with other agents targeting the PI3K-AKT-mTOR pathway .
26370156
The index patient has been treated with mTORC1/2 inhibitors that led to Cancertumor stabilization for more than 18 months.SIGNIFICANCE : RICTOR amplification may define a novel and unique molecular subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors .
26370156
The index patient has been treated with mTORC1/2 inhibitors that led to tumor stabilization for more than 18 months.SIGNIFICANCE : RICTOR amplification may define a novel and unique molecular subset of patients with Cancerlung cancer who may benefit from treatment with mTORC1/2 inhibitors .
26372703
BACKGROUND : Identifying patients who will experience Cancerlung cancer recurrence after surgery remains a challenge .
26372703
We aimed to evaluate whether mutant forms of epidermal growth factor receptor ( EGFR ) and CancerKirsten rat sarcoma viral oncogene homolog ( KRAS ) ( mEGFR and mKRAS ) are useful biomarkers in resected non small cell lung cancer ( NSCLC ) .
26372703
We aimed to evaluate whether mutant forms of epidermal growth factor receptor ( EGFR ) and Kirsten rat sarcoma viral oncogene homolog ( KRAS ) ( mEGFR and mKRAS ) are useful biomarkers in Cancerresected non small cell lung cancer ( NSCLC ) .
26372703
AdverseOutcomeRisk of recurrence was significantly lower for non KRAS G12V ( HR : 0.01 , ( 0.001-0 .08 ) , P < 0.0001 ) .
26372962
Oncogenic ROS1 fusion proteins are molecular drivers in Cancermultiple malignancies , including a subset of non small cell lung cancer ( NSCLC ) .
26372962
Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies , including a subset of Cancernon small cell lung cancer ( NSCLC ) .
26372962
The phylogenetic proximity of the ROS1 and Canceranaplastic lymphoma kinase ( ALK ) catalytic domains led to the clinical repurposing of the Food and Drug Administration ( FDA )-approved ALK inhibitor crizotinib as a ROS1 inhibitor .
26372962
Taken together , inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK driven NSCLC and Cancerother malignancies .
26391455
CancerProstate cancer ( PCa ) is the second leading cause of cancer related death in men ; however , the molecular mechanisms leading to its development and progression are not yet fully elucidated .
26391455
Prostate cancer ( PCa ) is the second leading cause of Cancercancer related death in men ; however , the molecular mechanisms leading to its development and progression are not yet fully elucidated .
26391455
We recently reported an inverse correlation between the activity of the STK11 and AMPK pathway and the MAPK and p38 cascade in CancerHIF1A dependent malignancies .
26392102
PURPOSE : To evaluate dabrafenib , a selective BRAF inhibitor , combined with trametinib , a selective MEK inhibitor , in patients with CancerBRAF V600-mutant metastatic colorectal cancer ( mCRC ) .
26392102
RESULTS : Of 43 patients , five ( 12 % ) achieved a partial response or better , including one ( 2 % ) complete response , with duration of response > 36 months ; 24 patients ( 56 % ) achieved Diseasestable disease as best confirmed response .
26392102
Mitogen activated protein kinase signaling was inhibited in all patients evaluated , but to a lesser degree than observed in CancerBRAF-mutant melanoma with dabrafenib alone .
26392102
Additional studies targeting the mitogen activated protein kinase pathway in this Diseasedisease are warranted .
26397223
CancerUveal melanoma ( UM ) is an aggressive intraocular malignancy with limited therapeutic options .
26397223
Uveal melanoma ( UM ) is an Canceraggressive intraocular malignancy with limited therapeutic options .
26397223
Chromatin regulators have become attractive targets for Cancercancer therapy .
26397223
In particular , the bromodomain and extra-terminal ( BET ) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and Cancersolid tumors .
26397223
In addition , administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of Cancertumor growth.Collectively , our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq and Gna11 mutations .
26398480
However , the contribution of OCT4B1 in the tumorigenesis and drug resistance of Cancercolon cancer remains to be determined .
26398480
The aim of the present study was to determine whether OCT4B1 , which maintains the stemness of ES cells , promoted cell growth by facilitating transition of the cell cycle and reduced apoptosis in Cancercolon cancer and drug resistant cells using flow cytometry and western blotting .
26398480
The results showed that , OCT4B1 promoted the growth of Cancercolon cancer and drug resistant cancer cells by maintaining the activity of ES cells and by facilitating the transition of the cell cycle and reducing apoptosis .
26398480
The results showed that , OCT4B1 promoted the growth of colon cancer and Cancerdrug resistant cancer cells by maintaining the activity of ES cells and by facilitating the transition of the cell cycle and reducing apoptosis .
26398480
Furthermore , OCT4B1 enhanced the ability of migration and invasion through alteration of the epithelial-to-mesenchymal transition ( EMT ) in Cancercolon cancer .
26398480
In conclusion , to the best of our knowledge , the results demonstrated for the first time that OCT4B1 functions as an oncogene in Cancercolon cancer and provides the development of novel therapeutic strategies to treat colon cancer , particularly drug resistance .
26398480
In conclusion , to the best of our knowledge , the results demonstrated for the first time that OCT4B1 functions as an oncogene in colon cancer and provides the development of novel therapeutic strategies to treat Cancercolon cancer , particularly drug resistance .
26422378
However , no studies to date have assessed variants of the GADD45 gene and their potential relationship to Cancertumor susceptibility .
26422378
We investigated the association of the GADD45A ( 1506T > C ) polymorphism with Cancerovarian cancer development in 258 ovarian cancer patients and 332 age matched healthy women as controls using sequence analysis .
26422378
We investigated the association of the GADD45A ( 1506T > C ) polymorphism with ovarian cancer development in 258 Cancerovarian cancer patients and 332 age matched healthy women as controls using sequence analysis .
26422378
We found a statistically significant difference in the GADD45A ( 1506T > C ) genotype distributions between the case and control groups ( TT vs. TC vs. CC , P = 0.0021 ) and found that variant 1506T > C was significantly associated with an AdverseOutcomeincreased risk of ovarian cancer ( P < 0.001 , OR = 1.71 , 95 % CI [ 1.28-2 .29 ] ) .
26422378
We found a statistically significant difference in the GADD45A ( 1506T > C ) genotype distributions between the case and control groups ( TT vs. TC vs. CC , P = 0.0021 ) and found that variant 1506T > C was significantly associated with an increased risk of Cancerovarian cancer ( P < 0.001 , OR = 1.71 , 95 % CI [ 1.28-2 .29 ] ) .
26422378
We observed a statistically significant effect between Cancertumor histology ( P = 0.032 ) and CA125 status ( P = 0.021 ) .
26422378
Carrying the C allele ( TC+CC ) was associated with an AdverseOutcomeincreased risk of positive CA125 ( OR = 3.20 , 95 % CI [ 1.15-8 .71 ) .
26422378
Carrying the T allele ( TT+TC ) showed a significant correlation with both higher GADD45A mRNA expression and Cancerlonger ovarian cancer RFS ( relapse-free survival ) and OS ( overall survival ) .
26422378
We are the first group to demonstrate that the GADD45A ( 1506T > C ) polymorphism is associated with Cancerovarian cancer susceptibility and prognosis .
26422378
These data suggest that GADD45A ( 1506T > C ) is a Cancernew tumor susceptibility gene and could be a useful molecular marker for assessing ovarian cancer risk and for predicting ovarian cancer patient prognosis .
26422378
These data suggest that GADD45A ( 1506T > C ) is a new tumor susceptibility gene and could be a useful molecular marker for assessing Cancerovarian cancer risk and for predicting ovarian cancer patient prognosis .
26422378
These data suggest that GADD45A ( 1506T > C ) is a new tumor susceptibility gene and could be a useful molecular marker for assessing ovarian cancer AdverseOutcomerisk and for predicting ovarian cancer patient prognosis .
26422378
These data suggest that GADD45A ( 1506T > C ) is a new tumor susceptibility gene and could be a useful molecular marker for assessing ovarian cancer risk and for predicting Cancerovarian cancer patient prognosis .
26423602
There are few effective treatments for Cancerrecurrent glioblastoma multiforme ( GBM ) .
26423602
Following Diseasedisease progression after 3 temozolomide cycles , the patient entered a phase I/II clinical trial of afatinib ( 20-40 mg daily for 28 days ) plus temozolomide ( 50 mg/m2 every 21/28 days ) .
26423602
Next generation sequencing analysis of the Cancerbrain tumor specimen was performed .
26423602
DiseaseSignificant disease regression was observed after 5 cycles and was maintained during long-term follow-up .
26428308
INTRODUCTION : Deletion of the tumor suppressor gene LRP1B has been reported in Cancerglioblastoma , the most aggressive primary brain tumor in adults .
26428308
INTRODUCTION : Deletion of the tumor suppressor gene LRP1B has been reported in glioblastoma , the most Canceraggressive primary brain tumor in adults .
26428308
CONCLUSION : LRP1B presents with frequent molecular alterations which impact patient outcome , highlighting the potential interest of this gene for Cancerglioblastoma patients .
26436839
Neomorphic mutations in isocitrate dehydrogenase 1 ( IDH1 ) are driver mutations in Canceracute myeloid leukemia ( AML ) and other cancers .
26436839
Neomorphic mutations in isocitrate dehydrogenase 1 ( IDH1 ) are driver mutations in acute myeloid leukemia ( AML ) and Cancerother cancers .
26436839
Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in Cancerleukemia .
26439803
PURPOSE : Although activating mutations in the epidermal growth factor receptor ( EGFR ) gene are predictive markers for response to EGFR inhibitors , 30-40 % of CancerEGFR-mutant non small cell lung cancer ( NSCLC ) patients are de novo non responders .
26439803
METHODS : We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases ( RTKs ) in Cancerstage IIIB-IV NSCLC tumors .
26439803
Analysis of Cancerbaseline tumor RTK profiles revealed that , regardless of EGFR mutation status , higher levels of EGFR relative to MET correlated with longer PFS .
26439803
CONCLUSION : The EGFR and MET ratio measured in Cancertumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors .
26442524
One major reason for the failure of Canceradvanced colorectal cancer ( CRC ) treatment is the occurrence of chemoresistance to fluoropyrimidine ( FU )-based chemotherapy .
26442524
CancerPrimary tumour specimens and adjacent non tumour sites were used to determine miR-218 expression distribution and explore its potential prognostic value in response to 5-FU-based treatment in patients with CRC .
26442524
Primary tumour specimens and Canceradjacent non tumour sites were used to determine miR-218 expression distribution and explore its potential prognostic value in response to 5-FU-based treatment in patients with CRC .
26444240
Here we report a novel isoform of the Canceranaplastic lymphoma kinase ( ALK ) that is expressed in ~ 11 % of melanomas and sporadically in other human cancer types , but not in normal tissues .
26444240
Here we report a novel isoform of the anaplastic lymphoma kinase ( ALK ) that is expressed in ~ 11 % of Cancermelanomas and sporadically in other human cancer types , but not in normal tissues .
26444240
Here we report a novel isoform of the anaplastic lymphoma kinase ( ALK ) that is expressed in ~ 11 % of melanomas and sporadically in Cancerother human cancer types , but not in normal tissues .
26444240
In ALK ( CancerATI )-expressing tumours , the ATI site is enriched for H3K4me3 and RNA polymerase II , chromatin marks characteristic of active transcription initiation sites .
26444240
ALK inhibitors can suppress the kinase activity of ALK ( ATI ) , suggesting that patients with ALK ( CancerATI )-expressing tumours may benefit from ALK inhibitors .
26444240
Our findings suggest a novel mechanism of oncogene activation in Cancercancer through de novo alternative transcription initiation .
26459177
MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in Cancerleukemias .
26459177
Thus , a phase I study of RG7112 in patients with Cancerhematologic malignancies was conducted .
26459177
Patients were divided into two cohorts : Stratum A [ relapsed and Cancerrefractory acute myeloid leukemia ( AML ; except acute promyelocytic leukemia ) , acute lymphoblastic leukemia , and chronic myelogenous leukemia ] and Stratum B ( relapsed and refractory chronic lymphocytic leukemia and small cell lymphocytic leukemia ; CLL and sCLL ) .
26459177
Patients were divided into two cohorts : Stratum A [ relapsed and refractory acute myeloid leukemia ( AML ; except Canceracute promyelocytic leukemia ) , acute lymphoblastic leukemia , and chronic myelogenous leukemia ] and Stratum B ( relapsed and refractory chronic lymphocytic leukemia and small cell lymphocytic leukemia ; CLL and sCLL ) .
26459177
Patients were divided into two cohorts : Stratum A [ relapsed and refractory acute myeloid leukemia ( AML ; except acute promyelocytic leukemia ) , Canceracute lymphoblastic leukemia , and chronic myelogenous leukemia ] and Stratum B ( relapsed and refractory chronic lymphocytic leukemia and small cell lymphocytic leukemia ; CLL and sCLL ) .
26459177
Patients were divided into two cohorts : Stratum A [ relapsed and refractory acute myeloid leukemia ( AML ; except acute promyelocytic leukemia ) , acute lymphoblastic leukemia , and Cancerchronic myelogenous leukemia ] and Stratum B ( relapsed and refractory chronic lymphocytic leukemia and small cell lymphocytic leukemia ; CLL and sCLL ) .
26459177
Patients were divided into two cohorts : Stratum A [ relapsed and refractory acute myeloid leukemia ( AML ; except acute promyelocytic leukemia ) , acute lymphoblastic leukemia , and chronic myelogenous leukemia ] and Stratum B ( relapsed and Cancerrefractory chronic lymphocytic leukemia and small cell lymphocytic leukemia ; CLL and sCLL ) .
26459177
Patients were divided into two cohorts : Stratum A [ relapsed and refractory acute myeloid leukemia ( AML ; except acute promyelocytic leukemia ) , acute lymphoblastic leukemia , and chronic myelogenous leukemia ] and Stratum B ( relapsed and refractory chronic lymphocytic leukemia and Cancersmall cell lymphocytic leukemia ; CLL and sCLL ) .
26459177
All patients experienced at least 1 adverse event , and 3 dose limiting Diseasetoxicities were reported .
26459177
DiseaseAntileukemia activity was observed in the 30 patients with AML assessed at the MTD , including 5 patients who met International Working Group ( IWG ) criteria for response .
26459177
We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in Cancerhematologic malignancies .
26459251
INTRODUCTION : The Canceresophageal squamous cell carcinoma ( ESCC ) is the predominant pathological type and accounts for more than 80 % of esophageal cancer in China .
26459251
INTRODUCTION : The esophageal squamous cell carcinoma ( ESCC ) is the predominant pathological type and accounts for more than 80 % of Canceresophageal cancer in China .
26459251
The successful use of anti-epidermal growth factor receptor ( EGFR ) treatment in head and Cancerneck squamous cell carcinoma provides the rationale for introducing anti-EGFR targeting treatment in ESCC .
26459251
RESULTS : Totally 55 Cancertumor samples were analyzed .
26459251
The expression of EGFR was not related to gender , age , Cancertumor location , tumor differentiation and clinical stage of disease .
26459251
The expression of EGFR was not related to gender , age , tumor location , Cancertumor differentiation and clinical stage of disease .
26459251
The expression of EGFR was not related to gender , age , tumor location , tumor differentiation and clinical stage of Diseasedisease .
26460303
PURPOSE : BRAF V600E mutation is seen in 5 % to 8 % of patients with Cancermetastatic colorectal cancer ( CRC ) and is associated with poor prognosis .
26460303
PURPOSE : BRAF V600E mutation is seen in 5 % to 8 % of patients with metastatic colorectal cancer ( CRC ) and is associated with AdverseOutcomepoor prognosis .
26460303
Vemurafenib , an oral BRAF V600 inhibitor , has pronounced activity in patients with Cancermetastatic melanoma , but its activity in patients with BRAF V600E positive metastatic CRC was unknown .
26460303
Grade 3 Diseasetoxicities included keratoacanthomas , rash , fatigue , and arthralgia .
26460303
Grade 3 toxicities included Cancerkeratoacanthomas , rash , fatigue , and arthralgia .
26460303
Of the 21 patients treated , one patient had a confirmed partial response ( 5 % ; 95 % CI , 1 % to 24 % ) and seven other patients had Diseasestable disease by RECIST criteria .
26460303
In contrast to prior expectations , concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients ' Cancertumors ( median , 0.21 % allele frequency ) and were apparent mechanisms of acquired resistance in vemurafenib sensitive patient derived xenograft models .
26460303
CONCLUSION : In marked contrast to the results seen in patients with CancerBRAF V600E-mutant melanoma , single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC .
26464169
In conclusion , the presence and number of mutated genes within the S/A/R panel are adversely associated with Diseaseadvanced disease and poor survival in KIT D816V ( + ) SM .
26486786
Myeloproliferative neoplasms are Diseaseclonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters , clinical evolution , and prognosis .
26486786
We report on the response to IFNalpha therapy in a cohort of 31 Diseaseessential thrombocythemia ( ET ) patients with CALR mutations ( mean follow-up of 11.8 years ) .
26490311
PURPOSE : mTOR is a validated target in Cancercancer .
26490311
It remains to be determined whether Cancermelanoma patients bearing mTOR mutation could be selected for treatment with PI3K-AKT-mTOR pathway inhibitors .
26490311
EXPERIMENTAL DESIGN : A total of 412 Cancermelanoma samples were included .
26490311
mTOR nonsynonymous mutations were relatively more frequent in acral ( 11.0 % ) and mucosal ( 14.3 % ) Cancermelanomas than in chronic sun induced damage ( CSD ; 6.7 % ) and non CSD ( 3.4 % ) melanomas .
26490311
mTOR nonsynonymous mutations were relatively more frequent in acral ( 11.0 % ) and mucosal ( 14.3 % ) melanomas than in chronic sun induced damage ( CSD ; 6.7 % ) and non CSD ( 3.4 % ) Cancermelanomas .
26490311
The median survival time for Cancermelanoma patients with mTOR nonsynonymous mutation was significantly shorter than that for patients without mTOR nonsynonymous mutation ( P = 0.028 ) .
26490311
CONCLUSIONS : mTOR nonsynonymous mutations are frequent in Cancermelanoma patients .
26490311
mTOR nonsynonymous mutation may predict a worse prognosis of Cancermelanoma .
26490311
Clinical trials with PI3K-AKT-mTOR pathway inhibitors may be beneficial for Cancermelanoma patients with specific mTOR mutations .
26502926
BACKGROUND : Although it has been suggested that a high level of thymidylate synthase ( TYMS ) gene expression in Cancermalignant tumors is related to reduced sensitivity to the antifolate drug pemetrexed , no direct evidence for such an association has been demonstrated in routine clinical samples from patients treated with the drug .
26502926
The purpose of this study was to quantitatively assess the impact of TYMS gene expression in Cancertumor cells as a predictor of the efficacy of pemetrexed therapy in patients with advanced non small cell lung cancer ( NSCLC ) treated at our institution .
26502926
The purpose of this study was to quantitatively assess the impact of TYMS gene expression in tumor cells as a predictor of the efficacy of pemetrexed therapy in patients with Canceradvanced non small cell lung cancer ( NSCLC ) treated at our institution .
26502926
CONCLUSIONS : TYMS overexpression in Cancertumor cells correlated with a reduced response to pemetrexed containing chemotherapy and might be used as a predictive biomarker in advanced NSCLC patients .
26508446
BACKGROUND : The anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies ( moAbs ) cetuximab or panitumumab are administered to Cancercolorectal cancer ( CRC ) patients who harbor wild-type RAS proto-oncogenes .
26508446
The application of parallel sequencing technology in clinical practice , in addition to its innate ability to simultaneously examine the genetic status of Cancerseveral cancer genes , proved to be more accurate and sensitive than the presently in use traditional approaches .
26510020
BACKGROUND : CancerProstate cancer is a heterogeneous disease , but current treatments are not based on molecular stratification .
26510020
BACKGROUND : Prostate cancer is a Diseaseheterogeneous disease , but current treatments are not based on molecular stratification .
26510020
We hypothesized that metastatic , Cancercastration resistant prostate cancers with DNA-repair defects would respond to poly ( adenosine diphosphate [ ADP ]-ribose ) polymerase ( PARP ) inhibition with olaparib .
26510020
METHODS : We conducted a phase 2 trial in which patients with metastatic , Cancercastration resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day .
26510020
The primary end point was the response rate , defined either as an objective response according to Response Evaluation Criteria in CancerSolid Tumors , version 1.1 , or as a reduction of at least 50 % in the prostate specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml .
26510020
Targeted next generation sequencing , exome and transcriptome analysis , and digital polymerase-chain-reaction testing were performed on samples from mandated Cancertumor biopsies .
26510020
Next generation sequencing identified homozygous deletions , deleterious mutations , or both in DNA-repair genes -- including BRCA1/2 , ATM , Fanconi 's Diseaseanemia genes , and CHEK2 -- in 16 of 49 patients who could be evaluated ( 33 % ) .
26510020
DiseaseAnemia ( in 10 of the 50 patients [ 20 % ] ) and fatigue ( in 6 [ 12 % ] ) were the most common grade 3 or 4 adverse events , findings that are consistent with previous studies of olaparib .
26510020
CONCLUSIONS : Treatment with the PARP inhibitor olaparib in patients whose Cancerprostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate .
26515464
EGFR mutated Cancerlung cancer accounts for a significant subgroup of non-small-cell lung cancer ( NSCLC ) .
26515464
EGFR mutated lung cancer accounts for a significant subgroup of Cancernon-small-cell lung cancer ( NSCLC ) .
26515464
The potency of 1st ( erlotinib ) , 2nd ( afatinib ) and 3rd ( osimertinib and rociletinib ) generation EGFR-TKIs was compared in vitro for Cancerhuman lung cancer cell lines and Ba/F3 cells , which exogenously express mutated or wild type EGFR .
26537256
Amplification of the MYCN oncogene predicts treatment resistance in Cancerchildhood neuroblastoma .
26537256
We used a MYC target gene signature that predicts Cancerpoor neuroblastoma prognosis to identify the histone chaperone FACT ( facilitates chromatin transcription ) as a crucial mediator of the MYC signal and a therapeutic target in the disease .
26537256
We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT ( facilitates chromatin transcription ) as a crucial mediator of the MYC signal and a therapeutic target in the Diseasedisease .
26537256
FACT and MYCN expression created a forward feedback loop in Cancerneuroblastoma cells that was essential for maintaining mutual high expression .
26537256
FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced Cancertumor initiation and progression in vivo .
26537256
CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs , thus creating a synthetic lethal environment in MYCN amplified Cancerneuroblastoma cells and suggesting a treatment strategy for MYCN driven neuroblastoma .
26537256
CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs , thus creating a synthetic lethal environment in MYCN amplified neuroblastoma cells and suggesting a treatment strategy for MYCN driven Cancerneuroblastoma .
26544513
HRAS is a frequently mutated oncogene in Cancercancer .
26544513
Here , we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in Cancervarious cancer cell lines including lung , bladder and esophageal cancer .
26544513
Here , we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung , bladder and Canceresophageal cancer .
26544513
Our results show that HRAS mutations in Cancercancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with HRAS mutant tumors .
26544513
Our results show that HRAS mutations in cancer activate the RAS and mTOR pathways which might serve as a therapeutic option for patients with CancerHRAS mutant tumors .
26546616
PURPOSE : To assess the Cancertumor response to the smoothened ( SMO ) inhibitor , sonidegib ( LDE225 ) , in patients with an advanced basal cell carcinoma ( BCC ) resistant to treatment with vismodegib ( GDC0449 ) .
26546616
PURPOSE : To assess the tumor response to the smoothened ( SMO ) inhibitor , sonidegib ( LDE225 ) , in patients with an Canceradvanced basal cell carcinoma ( BCC ) resistant to treatment with vismodegib ( GDC0449 ) .
26546616
CancerTumor response was determined using the response evaluation criteria in solid tumors .
26546616
Tumor response was determined using the response evaluation criteria in Cancersolid tumors .
26546616
Five patients experienced Diseaseprogressive disease with sonidegib .
26546616
Three patients experienced Diseasestable disease and discontinued sonidegib either due to adverse events ( n = 1 ) or due to election for surgery ( n = 2 ) .
26546616
Patients who have developed treatment resistance to an SMO inhibitor may continue to experience Cancertumor progression in response to other SMO inhibitors .
26547802
BACKGROUND : MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3 % of all Cancerlung adenocarcinomas .
26547802
Patients with Cancerlung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported .
26547802
Additionally , MET splice site mutations were analyzed in Cancerseveral cancers included in The Cancer Genome Atlas ( TCGA ) dataset .
26547802
Additionally , MET splice site mutations were analyzed in several cancers included in The CancerCancer Genome Atlas ( TCGA ) dataset .
26547802
In the TCGA dataset , Cancerlung adenocarcinomas had the highest incidence of MET exon 14 deletions , while other cancers rarely carried such mutations .
26547802
In the TCGA dataset , lung adenocarcinomas had the highest incidence of MET exon 14 deletions , while Cancerother cancers rarely carried such mutations .
26547802
Approximately 10 % of the Cancerlung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion .
26547802
CONCLUSIONS : These findings suggested that this system may be useful for experiments requiring the creation of specific mutations , and the present experimental findings encourage the development of MET targeted therapy against Cancerlung cancer carrying the MET exon 14 deletion .
26554404
CancerNeuroblastomas harboring activating point mutations in anaplastic lymphoma kinase ( ALK ) are differentially sensitive to the ALK inhibitor crizotinib , with certain mutations conferring intrinsic crizotinib resistance .
26554404
Neuroblastomas harboring activating point mutations in Canceranaplastic lymphoma kinase ( ALK ) are differentially sensitive to the ALK inhibitor crizotinib , with certain mutations conferring intrinsic crizotinib resistance .
26554404
Most importantly , PF-06463922 induces Cancercomplete tumor regression in both crizotinib resistant and crizotinib sensitive xenograft mouse models of neuroblastoma , as well as in patient derived xenografts harboring the crizotinib resistant F1174L or F1245C mutations .
26554404
Most importantly , PF-06463922 induces complete tumor regression in both crizotinib resistant and crizotinib sensitive xenograft mouse models of Cancerneuroblastoma , as well as in patient derived xenografts harboring the crizotinib resistant F1174L or F1245C mutations .
26554404
These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK mutated Cancerxenograft tumors , while also inducing responses in an R1275Q xenograft model .
26554404
Taken together , these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK mutated neuroblastoma.SIGNIFICANCE : The next generation ALK and ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK driven Cancerneuroblastoma models with primary crizotinib resistance .
26554404
Our biochemical and in vivo data provide the preclinical rationale for fast tracking the development of this agent in children with relapsed and Cancerrefractory ALK-mutant neuroblastoma .
26559459
Human epidermal growth factor 2 ( HER2 , ERBB2 ) mutations in Cancerlung cancers are oncogenic drivers that respond to HER2 targeted therapies .
26559459
Little is known about the sensitivity of subtypes of CancerHER2 mutant lung cancers to targeted agents .
26559459
We present a patient with CancerHER2 mutant lung cancer with a 12 base pair insertion YVMA ( p.A775 _ G776insYVMA ) , who had a long natural history and durable partial response to afatinib .
26559459
We demonstrate that afatinib has activity in patients with CancerHER2 mutant lung cancers with exon 20 YVMA insertions , the most common variant .
26565381
INTRODUCTION : Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 ( NTRK1 ) occur in a subset of Cancernon small cell lung cancers ( NSCLCs ) and other solid tumor malignancies , leading to expression of an oncogenic TrkA fusion protein .
26565381
INTRODUCTION : Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 ( NTRK1 ) occur in a subset of non small cell lung cancers ( NSCLCs ) and Cancerother solid tumor malignancies , leading to expression of an oncogenic TrkA fusion protein .
26565381
A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or Cancermetastatic tumors ( NCT02097810 ) .
26565381
A patient with stage IV Cancerlung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib .
26565381
CONCLUSIONS : Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement , indicating that entrectinib may be an effective therapy for Cancertumors with NTRK gene rearrangements , including those with central nervous system metastases .
26574622
Aberrant mutational activation of FGFR2 is associated with Cancerendometrial cancers ( ECs ) .
26574622
We therefore investigated the effects of AP24534 on Cancerendometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms .
26574622
AP24534 significantly inhibited the proliferation of Cancerendometrial cancer cells bearing activating FGFR2 mutations ( N549K , K310R and N549K , S252W ) and mainly induced G1/S cell cycle arrest leading to apoptosis .
26574622
Moreover , AP24534 inhibited migration and invasion of Cancerendometrial cancer cells with FGFR2 mutations .
26574622
In addition , AP24534 significantly blocked anchorage independent growth of Cancerendometrial cancer cells .
26589432
PURPOSE : ActivatingPIK3CAgenomic alterations are frequent in head and Cancerneck squamous cell carcinoma ( HNSCC ) , and there is an association between phosphoinositide 3-kinase ( PI3K ) signaling and radioresistance .
26596672
BACKGROUND : Patients with Canceradvanced HER2 positive breast cancer frequently develop CNS metastases .
26596672
We aimed to assess the efficacy and safety of afatinib , an irreversible blocker of the ErbB protein family , alone or combined with vinorelbine , compared with treatment of the investigator 's choice in women with CancerHER2 positive breast cancer with progressive brain metastases during or after treatment with trastuzumab , lapatinib , or both .
26596672
Women older than 18 years with histologically confirmed HER2 overexpressing Cancerbreast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors ( RECIST version 1.1 ) during or after treatment with trastuzumab , lapatinib , or both , were eligible .
26596672
Women older than 18 years with histologically confirmed HER2 overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in CancerSolid Tumors ( RECIST version 1.1 ) during or after treatment with trastuzumab , lapatinib , or both , were eligible .
26596672
We randomly assigned patients ( 1:1:1 ) centrally to afatinib 40 mg orally once per day , afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m ( 2 ) once per week , or investigator 's choice of treatment in cycles of 3 weeks until Diseasedisease progression , patient withdrawal , or unacceptable toxicity .
26596672
We randomly assigned patients ( 1:1:1 ) centrally to afatinib 40 mg orally once per day , afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m ( 2 ) once per week , or investigator 's choice of treatment in cycles of 3 weeks until disease progression , patient withdrawal , or Diseaseunacceptable toxicity .
26596672
The primary endpoint , assessed in the intention-to-treat population , was patient benefit at 12 weeks , defined by an absence of CNS or Diseaseextra-CNS disease progression , no tumour related worsening of neurological signs or symptoms , and no increase in corticosteroid dose .
26596672
The primary endpoint , assessed in the intention-to-treat population , was patient benefit at 12 weeks , defined by an absence of CNS or extra-CNS disease progression , no Cancertumour related worsening of neurological signs or symptoms , and no increase in corticosteroid dose .
26596672
The most common treatment related grade 3 or 4 adverse events were diarrhoea ( seven [ 18 % ] of 40 patients in the afatinib only group vs nine [ 24 % ] of 37 patients in the afatinib plus vinorelbine group vs two [ 5 % ] of 42 patients in the investigator 's choice group ) and Diseaseneutropenia ( none vs 14 [ 38 % ] vs four [ 10 % ] ) .
26596672
No further development of afatinib for CancerHER2 positive breast cancer is currently planned .
26596839
MyD88 was reported to be associated with paclitaxel sensitivity in Cancerlung cancer ; however , its roles in breast cancer remain unclear .
26596839
MyD88 was reported to be associated with paclitaxel sensitivity in lung cancer ; however , its roles in Cancerbreast cancer remain unclear .
26596839
The objective of this study is to investigate the expression and function of MyD88 in Cancerbreast cancer .
26596839
Immunohistochemistry ( IHC ) was used to analyze the expression of MyD88 in both Cancerbreast cancer tissues and adjacent normal tissues .
26596839
In Cancerbreast cancer tissues , the expression of MyD88 was significantly higher than that in tumor-adjacent normal tissues ( P < 0.001 ) .
26596839
Our data indicate that MyD88 may be a potential target molecule to be used in diagnosis and treatment of Cancerbreast cancer .
26598547
BACKGROUND : HER2 mutations have been identified as oncogenic drivers in Cancerlung cancers and are found in 1-2 % of lung adenocarcinomas .
26598547
BACKGROUND : HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2 % of Cancerlung adenocarcinomas .
26598547
PATIENTS AND METHODS : This retrospective cohort study in European centers assessed patients with Canceradvanced non-small-cell lung cancer ( NSCLC ) , a known HER2 exon-20 insertion , treated with chemotherapy and/or HER2 targeted drugs .
26598547
All Cancertumors were adenocarcinomas .
26598547
All tumors were Canceradenocarcinomas .
26617739
RIT1 , ( Ras like without CAAX1 ) , the founding member of a novel branch of the Ras subfamily , mediates a wide variety of cellular functions , including cell proliferation , survival , and differentiation , and it may play crucial oncogenic role in Cancerhuman cancer .
26617739
The purpose of the current study was to characterize the expression pattern of RIT1 and assess the clinical significance of RIT1 expression in Cancerendometrial cancer patients .
26617739
The mRNA and protein expression of RIT1 was significantly overexpressed in 7 Cancerendometrial cancer cell lines by qPCR and Western blot , respectively .
26617739
In addition , RIT1 mRNA expression was elevated in 36 freshly Cancerfrozen endometrial cancer tissues compared to 21 non cancerous endometrial tissue samples .
26617739
Immunohistochemistry was used to examine the protein expression of RIT1 in two tissue microarrays containing 257 cases of Cancertumor and 31 non tumor tissues , which showed that elevated expression of RIT1 was significantly correlated with pathological type , clinical stage , grade and vascular invasion .
26617739
Immunohistochemistry was used to examine the protein expression of RIT1 in two tissue microarrays containing 257 cases of tumor and 31 Cancernon tumor tissues , which showed that elevated expression of RIT1 was significantly correlated with pathological type , clinical stage , grade and vascular invasion .
26617739
Importantly , Kaplan-Meier survival analysis indicated that RIT1 expression was associated with overall survival of Cancerendometrial cancer patients .
26617739
Multivariate Cox regression analysis revealed that RIT1 expression was one of the independent prognostic factors for Cancerendometrial cancer patients .
26617739
Furthermore , RIT1 combined with other AdverseOutcomeclinicopathological risk factors was a more significant model in ROC curve comparison .
26617739
In conclusion , elevated expression of RIT1 may contribute to the progression of Cancerendometrial cancer and thus may serve as a novel prognostic marker and a promising molecular target for the treatment of endometrial cancer .
26617739
In conclusion , elevated expression of RIT1 may contribute to the progression of endometrial cancer and thus may serve as a novel prognostic marker and a promising molecular target for the treatment of Cancerendometrial cancer .
26621817
AdverseOutcomeHigh risk mutations in several genes predispose to both colorectal cancer ( CRC ) and endometrial cancer ( EC ) .
26621817
High risk mutations in several genes predispose to both Cancercolorectal cancer ( CRC ) and endometrial cancer ( EC ) .
26621817
High risk mutations in several genes predispose to both colorectal cancer ( CRC ) and Cancerendometrial cancer ( EC ) .
26621817
Using CRC and EC genome-wide association series , totalling 13,265 Cancercancer cases and 40,245 controls , we found that the protective allele [ G ] at one previously identified CRC polymorphism , rs2736100 near TERT , was associated with EC risk ( odds ratio ( OR ) = 1.08 , P = 0.000167 ) ; this polymorphism influences the risk of several other cancers .
26621817
Using CRC and EC genome-wide association series , totalling 13,265 cancer cases and 40,245 controls , we found that the protective allele [ G ] at one previously identified CRC polymorphism , rs2736100 near TERT , was associated with EC AdverseOutcomerisk ( odds ratio ( OR ) = 1.08 , P = 0.000167 ) ; this polymorphism influences the risk of several other cancers .
26621817
Using CRC and EC genome-wide association series , totalling 13,265 cancer cases and 40,245 controls , we found that the protective allele [ G ] at one previously identified CRC polymorphism , rs2736100 near TERT , was associated with EC risk ( odds ratio ( OR ) = 1.08 , P = 0.000167 ) ; this polymorphism influences the AdverseOutcomerisk of several other cancers .
26621817
Using CRC and EC genome-wide association series , totalling 13,265 cancer cases and 40,245 controls , we found that the protective allele [ G ] at one previously identified CRC polymorphism , rs2736100 near TERT , was associated with EC risk ( odds ratio ( OR ) = 1.08 , P = 0.000167 ) ; this polymorphism influences the risk of Cancerseveral other cancers .
26621817
Overall , however , there was no good evidence that the set of CRC polymorphisms was associated with EC AdverseOutcomerisk , and neither of two previously reported EC polymorphisms was associated with CRC risk .
26621817
Overall , however , there was no good evidence that the set of CRC polymorphisms was associated with EC risk , and neither of two previously reported EC polymorphisms was associated with CRC AdverseOutcomerisk .
26621817
A combined analysis revealed one genome-wide significant polymorphism , rs3184504 , on chromosome 12q24 ( OR = 1.10 , P = 7.23 x10 (-9) ) with shared effects on CRC and EC AdverseOutcomerisk .
26621817
This polymorphism , a missense variant in the gene SH2B3 , is also associated with haematological and Diseaseautoimmune disorders , suggesting that it influences cancer risk through the immune response .
26621817
This polymorphism , a missense variant in the gene SH2B3 , is also associated with haematological and autoimmune disorders , suggesting that it influences Cancercancer risk through the immune response .
26621817
This polymorphism , a missense variant in the gene SH2B3 , is also associated with haematological and autoimmune disorders , suggesting that it influences cancer AdverseOutcomerisk through the immune response .
26621817
Another polymorphism , rs12970291 near gene TSHZ1 , was associated with both CRC and EC ( OR = 1.26 , P = 4.82 x10 (-8) ) , with the alleles showing opposite effects on the AdverseOutcomerisks of the two cancers .
26621817
Another polymorphism , rs12970291 near gene TSHZ1 , was associated with both CRC and EC ( OR = 1.26 , P = 4.82 x10 (-8) ) , with the alleles showing opposite effects on the risks of the two Cancercancers .
26623049
A number of previous studies have reported that 30-50 % of patients with Cancercolorectal cancer ( CRC ) harbor Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations , which is a major predictive biomarker of resistance to epidermal growth factor ( EGFR )-targeted therapy .
26623049
A number of previous studies have reported that 30-50 % of patients with colorectal cancer ( CRC ) harbor CancerKirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations , which is a major predictive biomarker of resistance to epidermal growth factor ( EGFR )-targeted therapy .
26623049
Treatment with an anti-EGFR inhibitor is recommended for patients with CancerKRAS wild-type metastatic colorectal cancer ( mCRC ) .
26623049
Of the 98 patients , 23 ( 23.5 % ) had CancerKRAS p.G13D-mutated tumors , whereas 75 ( 76.5 % ) had tumors harboring other mutations .
26623049
Of the 98 patients , 23 ( 23.5 % ) had KRAS p.G13D-mutated tumors , whereas 75 ( 76.5 % ) had Cancertumors harboring other mutations .
26625204
AIMS : Antibodies targeting the checkpoint molecules programmed cell death 1 ( PD-1 ) and its ligand PD-L1 are emerging Cancercancer therapeutics .
26625204
We systematically investigated PD-1 and PD-L1 expression patterns in the Cancerpoor-prognosis tumor entity high-grade serous ovarian carcinoma .
26625204
METHODS : PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 Cancerprimary cancers both in cancer cells and in tumor infiltrating lymphocytes ( TILs ) .
26625204
METHODS : PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in Cancercancer cells and in tumor infiltrating lymphocytes ( TILs ) .
26625204
METHODS : PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in Cancertumor infiltrating lymphocytes ( TILs ) .
26625204
An in silico validation of mRNA data was performed in The CancerCancer Genome Atlas ( TCGA ) dataset .
26625204
RESULTS : PD-1 and PD-L1 expression in Cancercancer cells , CD3+ , PD-1+ , and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free ( PFS ) and overall survival ( OS ) , with all factors being significant for PFS ( p < 0.035 each ) , and most being significant for OS .
26625204
Most factors also had prognostic value that was independent from age , stage , and Cancerresidual tumor .
26625204
CONCLUSIONS : Despite their reported immune-modulatory function , high PD-1 and PD-L1 levels are indicators of a favorable prognosis in Cancerovarian cancer .
26625204
Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in Cancerhigh-grade serous ovarian carcinoma , which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity .
26625204
Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma , which is an argument for the evaluation of immune checkpoint inhibiting drugs in this Cancertumor entity .
26625312
STK11 is commonly mutated in Cancerlung cancer .
26625312
We conducted a retrospective high-throughput genotyping study in 567 Cancerresected non squamous non-small-cell lung cancer ( NSCLC ) patients .
26625312
In multivariate analysis , STK11ex1-2 mutations remained associated with a AdverseOutcomepoor prognosis ( P = .002 ) .
26625312
Finally using mRNAseq data from the TCGA cohort , we showed that a Cancerstroma derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors .
26625312
Finally using mRNAseq data from the TCGA cohort , we showed that a stroma derived AdverseOutcomepoor prognosis signature was enriched in STK11ex1-2 mutated tumors .
26625312
Finally using mRNAseq data from the TCGA cohort , we showed that a stroma derived poor prognosis signature was enriched in STK11ex1-2 mutated Cancertumors .
26625312
All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of Cancerlung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities .
26629066
Its mutation confers an AdverseOutcomeincreased risk of breast cancer .
26629066
Its mutation confers an increased risk of Cancerbreast cancer .
26629066
It has also been suggested to increase AdverseOutcomerisks of prostate cancer , but its involvement with this type of cancer has not been confirmed .
26629066
It has also been suggested to increase risks of Cancerprostate cancer , but its involvement with this type of cancer has not been confirmed .
26629066
It has also been suggested to increase risks of prostate cancer , but its involvement with this type of Cancercancer has not been confirmed .
26629066
METHODS : We performed a systematic review and meta-analysis to clarify the association between CHEK2 1100delC , IVS2 +1 G > A , I157T mutation and AdverseOutcomerisk of Prostate Cancer .
26629066
The overall meta-analysis demonstrated that the CHEK2 1100delC mutation ( OR 3.29 ; 95 % confidence interval : 1.85-5 .85 ; P = 0.00 ) and I157T missense mutation ( OR 1.80 ; 95 % confidence interval : 1.51-2 .14 ; P = 0.00 ) was associated with higher AdverseOutcomerisk of Prostate Cancer , and CHEK2 1100delC mutation is irrelevant to familial aggregation phenomenon of prostate cancer ( OR 1.59 ; 95 % confidence interval : 0.79-3 .20 ; P = 0.20 ) .
26629066
The overall meta-analysis demonstrated that the CHEK2 1100delC mutation ( OR 3.29 ; 95 % confidence interval : 1.85-5 .85 ; P = 0.00 ) and I157T missense mutation ( OR 1.80 ; 95 % confidence interval : 1.51-2 .14 ; P = 0.00 ) was associated with higher risk of Prostate Cancer , and CHEK2 1100delC mutation is irrelevant to familial aggregation phenomenon of Cancerprostate cancer ( OR 1.59 ; 95 % confidence interval : 0.79-3 .20 ; P = 0.20 ) .
26629066
CONCLUSION : CHEK2 1100delC mutation and I157T missense mutation in males indicates higher AdverseOutcomerisk of Prostate Cancer , but there 's no evidence to prove the CHEK2 1100delC mutation was associated with Familial prostate cancer .
26629066
CONCLUSION : CHEK2 1100delC mutation and I157T missense mutation in males indicates higher risk of Prostate Cancer , but there 's no evidence to prove the CHEK2 1100delC mutation was associated with CancerFamilial prostate cancer .
26634247
BACKGROUND : An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 ( ALDH1A2 ) and gene promoter methylation has been identified as a common feature of Canceroropharyngeal squamous cell carcinoma ( OPSCC ) .
26634247
The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in Cancerestablished tumor cell lines and in an orthotopic mouse xenograft model .
26634247
Functionally , ALDH1A2 expression and activity in Cancertumor cell lines were related to RA levels .
26634247
CancerXenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal like phenotype characterized by vimentin expression .
26634247
Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and Cancerprimary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal like phenotype characterized by vimentin expression .
26634247
CONCLUSIONS : This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and Cancerneck cancer and our data implicate that patients with ALDH1A2 ( low ) tumors might benefit from adjuvant treatment with retinoids .
26634247
CONCLUSIONS : This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2 ( low ) Cancertumors might benefit from adjuvant treatment with retinoids .
26637881
AIM : To assess the efficacy of targeting fibroblast growth factor receptor ( FGFR ) with the pan-FGFR inhibitor BGJ398 in a Cancergastric cancer ( GC ) model .
26637881
Results were validated in Cancersubcutaneous tumor models .
26637881
Results were confirmed in vivo with strongest efficacy on growth in CancerKKLS tumors and only minor impairment of TMK-1 lesions .
26646755
BACKGROUND : To investigate whether TP53 DNA mutational status impacts progression-free survival ( PFS ) in patients with Canceradvanced sarcomas ( soft tissue sarcoma ) treated with vascular endothelial growth factor receptors ( VEGFR ) inhibition .
26646755
BACKGROUND : To investigate whether TP53 DNA mutational status impacts progression-free survival ( PFS ) in patients with advanced sarcomas ( Cancersoft tissue sarcoma ) treated with vascular endothelial growth factor receptors ( VEGFR ) inhibition .
26646755
PATIENTS AND METHODS : We retrospectively reviewed 19 cases of patients treated at the Ohio State James Comprehensive Cancer Center with Canceradvanced sarcoma treated with VEGFR inhibition who also had next generation sequencing of their tumors ( via FoundationOne Heme panel ) .
26646755
PATIENTS AND METHODS : We retrospectively reviewed 19 cases of patients treated at the Ohio State James Comprehensive Cancer Center with advanced sarcoma treated with VEGFR inhibition who also had next generation sequencing of their Cancertumors ( via FoundationOne Heme panel ) .
26646755
The PFS of patients with TP53 mutations was significantly greater than CancerTP53 wild-type tumors with the median PFS of 208 versus 136 days , respectively [ P = 0.036 , hazards ratio 0.38 ( 95 % confidence interval 0.09-0 .83 ) ] .
26646755
CONCLUSIONS : Mutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with Canceradvanced sarcoma .
26662432
microRNA-218 ( miR-218 ) is a vertebrate specific miRNA that plays a crucial role in tumorigenesis and Cancertumor progression .
26662432
This study analyzed the miR-218 expression level and clinical significance in Cancerpancreatic cancer .
26662432
One hundred and seven pairs of Cancerpancreatic cancer and adjacent normal tissues were analyzed by quantitative reverse-transcriptase polymerase chain reaction .
26662432
The relative expression of miR-218 in Cancerpancreatic cancer tissues ( 2.63 +/- 1.59 ) was significantly lower than that in matched noncancerous pancreatic tissues ( 6.52 +/- 2.50 , P < 0.001 ) .
26662432
The low expression of miR-218 in the Cancerpancreatic cancer tissues were strongly correlated with the TNM classification ( P = 0.02 ) , distant metastasis ( P = 0.001 ) , and tumor differentiation ( P = 0.003 ) .
26662432
The low expression of miR-218 in the pancreatic cancer tissues were strongly correlated with the TNM classification ( P = 0.02 ) , Cancerdistant metastasis ( P = 0.001 ) , and tumor differentiation ( P = 0.003 ) .
26662432
The low expression of miR-218 in the pancreatic cancer tissues were strongly correlated with the TNM classification ( P = 0.02 ) , distant metastasis ( P = 0.001 ) , and Cancertumor differentiation ( P = 0.003 ) .
26662432
The low level of miR-218 expression was significantly correlated with the shorter overall survival time of Cancerpancreatic cancer patients ( 5-year overall survival rate : 7.5 vs 34.9 % ; log-rank test : P < 0.001 ) .
26662432
Multivariate analyses confirmed that a low level of miR-218 expression was an independent predictor of AdverseOutcomepoor prognosis in pancreatic cancer patients ( Hazard ratio : 7.24 ; 95 % confidence interval : 2.01-18 .28 ; P = 0.007 ) .
26662432
Multivariate analyses confirmed that a low level of miR-218 expression was an independent predictor of poor prognosis in Cancerpancreatic cancer patients ( Hazard ratio : 7.24 ; 95 % confidence interval : 2.01-18 .28 ; P = 0.007 ) .
26662432
Our findings suggested a significant downregulation in the expression of miR-218 ; this might have considerable potential value in the prognosis for Cancerpancreatic cancer .
26664143
BACKGROUND : The association between the expression of programmed cell death-ligand 1 ( PD-L1 ) and survival in patients with Cancernon-small-cell lung cancer ( NSCLC ) is controversial .
26664143
However , a subgroup analysis showed a significant association between PD-L1 expression and AdverseOutcomepoor prognosis in Chinese patients with NSCLC ( HR = 1.55 , 95 % CI : 1.04-2 .29 , P = 0.03 ) .
26668065
BACKGROUND : CancerPancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor ( EGFR ) and other EGFR family members such as HER2 and ErbB2 .
26668065
The EGFR inhibitor erlotinib is approved for treatment of Cancerpancreatic cancer , but has shown modest activity in most patients .
26668065
OBJECTIVE : Here we investigated the activity of afatinib , a second generation irreversible pan-EGFR family kinase inhibitor , alone or in combination with ionizing radiation , toward Cancerpancreatic cancer cells .
26668065
CONCLUSIONS : Afatinib showed cytotoxic and radiosensitizing effects toward a subset of Cancerpancreatic cancer cells which was closely correlated with expression of EGFR , HER2 , and HER3 receptors , but not with KRAS status .
26671993
We hypothesized that decreased expression of SMARCA4 and BRG1 , a known regulator of transcription and DNA repair , is a novel predictive biomarker of increased sensitivity to adjuvant platinum based therapies in Cancernon small cell lung cancer ( NSCLC ) .
26671993
Kaplan-Meier method and log-rank tests were used to estimate and test the differences of probabilities in overall survival ( OS ) and Diseasedisease specific survival ( DSS ) between expression groups and treatment arms .
26671993
In multivariate analysis , compared with low , high SMARCA4 expression predicted a decrease in AdverseOutcomerisk of death [ HR , 0.6 ; 95 % confidence interval ( CI ) , 0.4-0 .8 ; P = 0.002 ] .
26673008
Fibroblast growth factor receptor 1 ( FGFR1 ) has been suggested to be the candidate gene for 8p11-12 amplification in Cancerbreast cancer and its therapeutic / prognostic value is explored .
26673008
We evaluated FGFR1 expression in a large cohort of Cancerbreast cancer by immunohistochemistry , correlated with the tumor clinic-pathologic features , biomarkers expression , and patient 's survival .
26673008
We evaluated FGFR1 expression in a large cohort of breast cancer by immunohistochemistry , correlated with the Cancertumor clinic-pathologic features , biomarkers expression , and patient 's survival .
26673008
FGFR1 expression was associated mainly with Cancerluminal cancers , particularly luminal B subtype ( 23.5 % ; p < 0.001 ) , and it also showed adverse prognostic impact on luminal A cancers .
26673008
FGFR1 expression was associated mainly with luminal cancers , particularly luminal B subtype ( 23.5 % ; p < 0.001 ) , and it also showed adverse prognostic impact on Cancerluminal A cancers .
26673008
FGFR1 expression was associated with higher pN ( p = 0.023 ) , pT ( p = 0.003 ) stages , lymphovascular invasion ( p = 0.010 ) , p-cadherin ( p = 0.028 ) , synaptophysin ( p = 0.009 ) and SOX2 expression ( p = 0.034 ) in Cancerluminal A cancers .
26673008
CancerFGFR1 expressing luminal A cancers showed a similar outcome as luminal B cancers .
26673008
FGFR1 expressing luminal A cancers showed a similar outcome as Cancerluminal B cancers .
26673008
Multivariate Cox regression analysis demonstrated FGFR1 positive luminal A Cancercancers to be an independently poor prognosticator for disease free survival in luminal cancers ( hazard ratio = 3.341 , p = 0.008 ) .
26673008
Multivariate Cox regression analysis demonstrated FGFR1 positive luminal A cancers to be an independently poor prognosticator for Diseasedisease free survival in luminal cancers ( hazard ratio = 3.341 , p = 0.008 ) .
26673008
Multivariate Cox regression analysis demonstrated FGFR1 positive luminal A cancers to be an independently poor prognosticator for disease free survival in Cancerluminal cancers ( hazard ratio = 3.341 , p = 0.008 ) .
26673008
Thus FGFR1 could be useful in identifying the aggressive cases amongst Cancerheterogeneous luminal A cancers .
26673008
Given the relevance of FGFR pathway in treatment resistance in Cancerluminal cancers , FGFR1 could be an important tumor biomarker and adverse prognostic factor potentially exploitable in the clinical management of luminal cancers .
26673008
Given the relevance of FGFR pathway in treatment resistance in luminal cancers , FGFR1 could be an Cancerimportant tumor biomarker and adverse prognostic factor potentially exploitable in the clinical management of luminal cancers .
26673008
Given the relevance of FGFR pathway in treatment resistance in luminal cancers , FGFR1 could be an important tumor biomarker and adverse prognostic factor potentially exploitable in the clinical management of Cancerluminal cancers .
26674132
It has been postulated that MMRD increases Cancertumor antigenicity and highlights a role for immunotherapeutic approach MMR deficient cancers .
26674132
It has been postulated that MMRD increases tumor antigenicity and highlights a role for Cancerimmunotherapeutic approach MMR deficient cancers .
26674132
This strategy was pursued in a patient with Cancerupper tract urothelial carcinoma , and the results are reported here .
26674132
A patient with sporadic , Cancerhigh grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy , and 340 VUS alterations .
26674132
A patient with sporadic , high grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of Cancermalignancy , and 340 VUS alterations .
26674132
CONCLUSION : Given their ability to generate neo-antigens , CancerMMR deficient cancers may be uniquely susceptible to immune checkpoint inhibitor strategies , including urothelial tract cancers .
26674132
CONCLUSION : Given their ability to generate neo-antigens , MMR deficient cancers may be uniquely susceptible to immune checkpoint inhibitor strategies , including Cancerurothelial tract cancers .
26674132
Screening for CancerMMR deficient cancers has the potential to become a routine strategy for evaluating the role of PD-L1 inhibitors for patient with advanced disease .
26674132
Screening for MMR deficient cancers has the potential to become a routine strategy for evaluating the role of PD-L1 inhibitors for patient with Diseaseadvanced disease .
26674738
In search for genes associated with Cancerhepatocellular carcinoma ( HCC ) by cDNA microarray , we found that KIF23 was upregulated in HCC tissues .
26674738
At present , much less is known about its expression and functions in Cancertumor cells .
26678033
Intrinsic cross-resistance to inhibition of different signaling pathways may hamper development of combinatorial treatments in Cancermelanoma , but the relative frequency of this phenotype and the strategies to overcome this hurdle remain poorly understood .
26678033
Among 49 CancerBRAF-mutant melanoma cell lines from patients not previously treated with target therapy , 21 ( 42.9 % ) showed strong primary resistance ( IC50 > 1 muM ) to a BRAFV600E inhibitor .
26678033
Primary cross-resistance was confirmed in an independent set of 23 CancerBRAF-mutant short-term melanoma cell cultures .
26678033
This was shown by extensive drug interaction analysis , Cancertumor growth inhibition assays in-vivo , p-ERK and p-AKT inhibition , promotion of melanoma apoptosis , apoptosis related protein modulation , activation of effector caspases and selective modulation of genes involved in melanoma drug resistance and belonging to the ERK and MAPK and PI3K and AKT canonical pathways .
26678033
This was shown by extensive drug interaction analysis , tumor growth inhibition assays in-vivo , p-ERK and p-AKT inhibition , promotion of Cancermelanoma apoptosis , apoptosis related protein modulation , activation of effector caspases and selective modulation of genes involved in melanoma drug resistance and belonging to the ERK and MAPK and PI3K and AKT canonical pathways .
26678033
This was shown by extensive drug interaction analysis , tumor growth inhibition assays in-vivo , p-ERK and p-AKT inhibition , promotion of melanoma apoptosis , apoptosis related protein modulation , activation of effector caspases and selective modulation of genes involved in Cancermelanoma drug resistance and belonging to the ERK and MAPK and PI3K and AKT canonical pathways .
26678033
Compared to co-targeting of mutant BRAF and PI3K and mTOR , the association of a MEK1/2 and a PI3K and mTOR inhibitor was more effective in the activation of Bax and of caspase-3 and in the induction of Cancercaspase dependent melanoma apoptosis .
26678033
These results suggest that intrinsic resistance to BRAF inhibition is frequently associated with primary cross-resistance to MEK and PI3K and mTOR blockade in CancerBRAF-mutant melanoma and provide pre-clinical evidence for a combinatorial approach to counteract this phenotype .
26683709
Enhancer of zeste homologue 2 ( EZH2 ) is a potential independent mechanism for epigenetic silencing of tumor suppressor genes in Cancercancer .
26683709
High EZH2 expression was significantly associated with poorer prognosis [ overall survival : HR 1.54 ( 95 % CI : 1.30-1 .78 ) , P < 0.000 ; Diseasedisease free survival : HR 1.35 ( 95 % CI : 1.00-1 .71 ) , P < 0.000 ] .
26683709
In Cancerbreast cancer , high EZH2 expression correlated with histological types [ OR : 1.53 ( 95CI : 1.13-2 .06 ) ; P < 0.006 ] , histological grade [ OR : 1.62 ( 95CI : 1.35-1 .95 ) ; P < 0.000 ] , estrogen receptor ( ER ) negativity [ OR : 2.05 ( 95CI : 1.67-2 .52 ) ; P < 0.000 ] , progesterone receptor ( PgR ) negativity [ OR : 1.42 ( 95CI : 1.03-1 .96 ) ; P = 0.034 ] , HER-2 positivity [ OR : 1.35 ( 95CI : 1.08-1 .69 ) ; P = 0.009 ] , and high p53 expression [ OR : 1.66 ( 95CI : 1.07-2 .59 ) ; P = 0.024 ] .
26683709
These results suggest that high EZH2 expression may be a promising prognostic factor to Cancerdifferent cancers .
26683709
High EZH2 expression tends to correlate with pathological types , histological grade , ER negativity , PgR negativity , HER-2 positivity and p53 high expression in Cancerbreast cancer .
26686064
The receptor tyrosine kinase RET is implicated in the progression of Cancerluminal breast cancers ( BC ) but its role in estrogen receptor ( ER ) negative tumors is unknown .
26686064
The receptor tyrosine kinase RET is implicated in the progression of luminal breast cancers ( BC ) but its role in estrogen receptor ( ER ) Cancernegative tumors is unknown .
26686064
Here we investigated the expression of RET in Cancerbreast cancer patients tumors and patient derived xenografts ( PDX ) and evaluated the therapeutic potential of Vandetanib , a tyrosin kinase inhibitor with strong activity against RET , EGFR and VEGFR2 , in ER negative breast cancer PDX .
26686064
Here we investigated the expression of RET in breast cancer patients tumors and patient derived xenografts ( PDX ) and evaluated the therapeutic potential of Vandetanib , a tyrosin kinase inhibitor with strong activity against RET , EGFR and VEGFR2 , in CancerER negative breast cancer PDX .
26686064
The RT-PCR analysis of RET expression in Cancerbreast tumors of 446 patients and 57 PDX , showed elevated levels of RET in ER+ and HER2+ subtypes and in a small subgroup of triple negative breast cancers ( TNBC ) .
26686064
The RT-PCR analysis of RET expression in breast tumors of 446 patients and 57 PDX , showed elevated levels of RET in ER+ and HER2+ subtypes and in a small subgroup of Cancertriple negative breast cancers ( TNBC ) .
26686064
Vandetanib induced Cancertumor regression in PDX models with high expression of RET or EGFR .
26686064
In a PDX model with no expression of RET nor EGFR , Vandetanib slowed Cancertumor growth without inducing tumor regression .
26686064
In a PDX model with no expression of RET nor EGFR , Vandetanib slowed tumor growth without inducing Cancertumor regression .
26686064
In addition , treatment by Vandetanib decreased expression of murine Vegf receptors and the endothelial marker Cd31 in the four PDX models tested , suggesting inhibition of Cancertumor vascularization .
26686064
In summary , these preclinical results suggest that Vandetanib treatment could be useful for patients with CancerER negative breast cancers overexpressing Vandetanib 's main targets .
26689995
Somatic mutations found within the tyrosine kinase domain ( TKD ) of the human epidermal growth factor ( HER ) family of receptors have been implicated in the development and progression of Cancernon small cell lung cancer ( NSCLC ) .
26689995
Taken together , these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation , in Cancerother cancers that more frequently carry somatic HER3 mutations .
26693073
An important determinant of the pathogenesis and prognosis of Diseasevarious diseases is inherited genetic variation .
26693073
Here we show that a common variant in the gene MTHFR [ rs1801133 ( C > T ) ] not only influences response to neoadjuvant chemoradiotherapy in patients with Cancerrectal cancer , but it also influences recurrence of the disease itself .
26693073
Here we show that a common variant in the gene MTHFR [ rs1801133 ( C > T ) ] not only influences response to neoadjuvant chemoradiotherapy in patients with rectal cancer , but it also influences recurrence of the Diseasedisease itself .
26693073
More specifically , patients with the homozygous ancestral ( wild type ) genotype ( C/C ) were 2.91 times more likely ( 291 % increased benefit ) to respond to neoadjuvant chemoradiotherapy { 95 % CI : [ 1.23 , 6.89 ] ; P = 0.0150 } and 3.25 times more likely ( 325 % increased benefit ) not to experience recurrence of the Diseasedisease { 95 % CI : [ 1.37 , 7.72 ] ; P = 0.0079 } than patients with either the heterozygous ( C/T ) or the homozygous mutation ( T/T ) genotype .
26693073
These results identify MTHFR as an important genetic marker and open up new , pharmacogenomic strategies in the treatment and management of Cancerrectal cancer .
26698910
In a patient who had Cancermetastatic anaplastic lymphoma kinase ( ALK )-rearranged lung cancer , resistance to crizotinib developed because of a mutation in the ALK kinase domain .
26698910
In a patient who had metastatic anaplastic lymphoma kinase ( CancerALK )-rearranged lung cancer , resistance to crizotinib developed because of a mutation in the ALK kinase domain .
26698910
Her Cancertumor did not respond to a second generation ALK inhibitor , but it did respond to lorlatinib ( PF-06463922 ) , a third generation inhibitor .
26698910
When her Cancertumor relapsed , sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation .
26698910
When her tumor relapsed , sequencing of the Cancerresistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation .
26698910
However , L1198F paradoxically enhances binding to crizotinib , negating the effect of C1156Y and resensitizing Cancerresistant cancers to crizotinib .
26698910
The patient received crizotinib again , and her Cancercancer related symptoms and liver failure resolved .
26701727
CancerHepatocellular carcinoma ( HCC ) is the fifth most common type of cancers worldwide .
26701727
Hepatocellular carcinoma ( HCC ) is the fifth most common type of Cancercancers worldwide .
26701727
However , current therapeutic approaches for this Diseaseepidemic disease are limited , and its 5-year survival rate has n't been improved in the past decades .
26701727
Patient derived xenograft ( PDX ) Cancertumor models have become an excellent in vivo system for understanding of disease biology and drug discovery .
26701727
Patient derived xenograft ( PDX ) tumor models have become an excellent in vivo system for understanding of Diseasedisease biology and drug discovery .
26701727
Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib treated Cancertumor tissues was significantly suppressed .
26708155
BACKGROUND : Alectinib -- a highly selective , CNS-active , ALK inhibitor showed promising clinical activity in crizotinib-naive and crizotinib resistant patients with ALK rearranged ( ALK positive ) Cancernon-small-cell lung cancer ( NSCLC ) .
26708155
The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in CancerSolid Tumors , version 1.1 .
26708155
Response endpoints were assessed in the response-evaluable population ( ie , patients with Diseasemeasurable disease at baseline who received at least one dose of study drug ) , and efficacy and safety analyses were done in the intention-to-treat population ( all enrolled patients ) .
26708155
At the time of the primary analysis ( median follow-up 4.8 months [ IQR 3.3-7 .1 ] ) , 33 of 69 patients with Diseasemeasurable disease at baseline had a confirmed partial response ; thus , the proportion of patients achieving an objective response by the independent review committee was 48 % ( 95 % CI 36-60 ) .
26708155
Two patients died : one had a haemorrhage ( judged related to study treatment ) , and one had Diseasedisease progression and a history of stroke ( judged unrelated to treatment ) .
26708155
Therefore , alectinib could be a suitable treatment for patients with DiseaseALK positive disease who have progressed on crizotinib .
26709701
In non clinical studies , the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of Cancersolid tumor cell lines in vitro .
26709701
In contrast , antitumor activity in Cancerxenograft tumors is model dependent , with some solid tumors showing no response to ixazomib .
26709701
In contrast , antitumor activity in xenograft tumors is model dependent , with some Cancersolid tumors showing no response to ixazomib .
26709701
A survey of 14 Cancernon small cell lung cancer ( NSCLC ) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype ; tumors with wild-type ( WT ) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations .
26709701
A survey of 14 non small cell lung cancer ( NSCLC ) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype ; Cancertumors with wild-type ( WT ) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations .
26709701
A survey of 14 non small cell lung cancer ( NSCLC ) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype ; tumors with wild-type ( WT ) KRAS were more sensitive to ixazomib than Cancertumors harboring KRAS activating mutations .
26709701
To confirm the association between KRAS genotype and ixazomib sensitivity , we used CancerSW48 isogenic colon cancer cell lines .
26709701
CancerSW48 KRAS WT tumors , but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors , were sensitive to ixazomib in vivo .
26709701
SW48 KRAS WT tumors , but neither CancerSW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors , were sensitive to ixazomib in vivo .
26709701
SW48 KRAS WT tumors , but neither SW48-KRAS-G13D tumors nor CancerSW48-KRAS-G12V tumors , were sensitive to ixazomib in vivo .
26709701
Since activated KRAS is known to be associated with metabolic reprogramming , we compared metabolite profiling of SW48-WT and CancerSW48-KRAS-G13D tumors treated with or without ixazomib .
26709701
Prior to treatment there were significant metabolic differences between SW48 WT and CancerSW48-KRAS-G13D tumors , reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors .
26709701
Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors , reflecting higher oxidative stress and glucose utilization in the CancerKRAS-G13D tumors .
26709701
Ixazomib treatment resulted in significant metabolic regulation , and some of these changes were specific to CancerKRAS WT tumors .
26709701
Depletion of free amino acid pools and activation of GCN2-eIF2alpha-pathways were observed both in Cancertumor types .
26709701
However , changes in lipid beta oxidation were observed in only the CancerKRAS WT tumors .
26712222
PURPOSE : We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus ( HPV ) and p16 protein expression status with outcomes in patients with Canceroropharyngeal carcinoma ( OPC ) receiving radiotherapy ( RT ) plus cetuximab or RT alone .
26712222
RESULTS : CancerTumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study ; 41 % were p16 positive .
26712222
The addition of cetuximab to RT increased LRC , OS , and PFS in both patients with p16 positive OPC and those with Diseasep16 negative disease .
26712909
Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of Diseaselate onset myelodysplastic syndrome ( MDS ) and/or acute myeloid leukemia ( AML ) , suggesting that DDX41 acts as a tumor suppressor .
26712909
Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome ( MDS ) and/or Canceracute myeloid leukemia ( AML ) , suggesting that DDX41 acts as a tumor suppressor .
26712909
To determine whether novel DDX41 mutations could be identified in families with additional types of Cancerhematologic malignancies , our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes .
26712909
To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies , our group screened two cohorts of families with a diverse range of Cancerhematologic malignancy subtypes .
26712909
As previously observed , MDS and AML were the most Cancercommon malignancies , often of the erythroblastic subtype , and 1 family displayed early-onset follicular lymphoma .
26712909
As previously observed , MDS and AML were the most common malignancies , often of the erythroblastic subtype , and 1 family displayed Cancerearly-onset follicular lymphoma .
26712909
We also show that most asymptomatic mutation carriers have normal blood counts until Cancermalignancy develops .
26712909
With an increasing number of both inherited and acquired mutations in this gene being identified , further study of how DDX41 disruption leads to Cancerhematologic malignancies is critical .
26715889
Palbociclib , an oral small-molecule inhibitor of cyclin dependent kinases 4 and 6 , was recently approved by the U.S. Food and Drug Administration in combination with letrozole for postmenopausal women with advanced hormone receptor positive , Cancerher2 negative breast cancer .
26715889
Here , we report a patient with metastatic estrogen receptor- positive , Cancerher2 negative breast cancer with CDKN2A loss who experienced a clinical response to palbociclib .
26716414
The identification and clinical validation of Cancercancer driver genes are essential to accelerate the translational transition of cancer genomics , as well as to find clinically confident targets for the therapeutic intervention of cancers .
26716414
The identification and clinical validation of cancer driver genes are essential to accelerate the translational transition of Cancercancer genomics , as well as to find clinically confident targets for the therapeutic intervention of cancers .
26716414
The identification and clinical validation of cancer driver genes are essential to accelerate the translational transition of cancer genomics , as well as to find clinically confident targets for the therapeutic intervention of Cancercancers .
26716414
Here we identified recurrent LMNA-NTRK1 and TPM3-NTRK1 fusions in Korean patients with Cancercolon cancer ( 3 out of 147 , 2 % ) through next generation RNA sequencing ( RNA-seq ) .
26716414
NTRK1 fusions were mutually exclusive oncogenic drivers of Cancercolon cancer that were accompanied with in vitro potential of colony formation and in vivo tumorigenicity comparable to KM12 , a human colon cancer cell line harboring TPM3-NTRK1 fusion .
26716414
NTRK1 fusions were mutually exclusive oncogenic drivers of colon cancer that were accompanied with in vitro potential of colony formation and in vivo tumorigenicity comparable to KM12 , a Cancerhuman colon cancer cell line harboring TPM3-NTRK1 fusion .
26716414
Korean patients with CancerTrkA positive colon cancer had a marginal but significant shorter overall survival time than TrkA negative colon cancer [ hazard ratio ( HR ) = 0.5346 , 95 % confidential interval ( CI ) = 0.2548-0 .9722 , p = 0.0411 ] .
26716414
Korean patients with TrkA positive colon cancer had a marginal but significant shorter overall survival time than CancerTrkA negative colon cancer [ hazard ratio ( HR ) = 0.5346 , 95 % confidential interval ( CI ) = 0.2548-0 .9722 , p = 0.0411 ] .
26716414
These results demonstrate that NTRK1 fusion is granted as a clinically relevant target for therapeutic intervention of Cancercolon cancer .
26722081
BACKGROUND : Tyrosine kinase inhibitors ( TKIs ) targeting epidermal growth factor receptor ( EGFR ) represent novel , effective tools in the management of Canceradvanced-stage non small cell lung cancer ( NSCLC ) .
26724472
MMNG HOS Transforming gene ( MET ) is an important driver gene in Cancernon small cell lung cancer .
26724472
MET copy number gain ( MCNG ) is an independent negative prognostic factor in Cancernon small cell lung cancer .
26724472
Here we report a patient with Cancerlung adenocarcinoma with MCNG but without a high-level MET and CEP7 ratio or METex14 splicing mutations who achieved a rapid response to crizotinib , indicating that MCNG may be an independent predictivebiomarker for response to MET inhibitors .
26725216
Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in CancerRAS-mutant cancers .
26725216
We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of CancerKRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase ( PI3K ) inhibition caused synergistic cell death .
26729184
Osimertinib ( Tagrisso ( ( TM ) ) , AZD9291 ) is an oral , third generation epidermal growth factor receptor tyrosine kinase inhibitor ( EGFR TKI ) that is being developed by AstraZeneca for the treatment of Canceradvanced non small cell lung cancer ( NSCLC ) .
26729184
Phase I trials in patients with Canceradvanced solid tumours are also being conducted .
26729443
PURPOSE : CancerNon-small-cell lung cancers ( NSCLCs ) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors .
26729443
We sought to describe the clinical , pathologic , and genomic characteristics of patients with Cancercancer with MET exon 14 mutations .
26729443
PATIENTS AND METHODS : We interrogated next generation sequencing results from 6,376 Cancercancers to identify those harboring MET exon 14 mutations .
26729443
RESULTS : MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs ( 3.0 % ) and were not seen in Cancerother cancer types in this study .
26729443
A patient whose Cancerlung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib .
26732095
We have identified previously undiscovered BRAF in-frame deletions near the alphaC-helix region of the kinase domain in pancreatic , lung , ovarian , and Cancerthyroid cancers .
26732095
These deletions are mutually exclusive with KRAS mutations and occur in 4.21 % of CancerKRAS wild-type pancreatic cancer .
26732095
In Cancertumor models with BRAF deletions , LY3009120 has shown tumor growth regression , whereas vemurafenib is inactive.SIGNIFICANCE : This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells .
26732095
In tumor models with BRAF deletions , LY3009120 has shown Cancertumor growth regression , whereas vemurafenib is inactive.SIGNIFICANCE : This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells .
26732095
In tumor models with BRAF deletions , LY3009120 has shown tumor growth regression , whereas vemurafenib is inactive.SIGNIFICANCE : This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in Cancertumor cells .
26732095
LY3009120 is active against these cells and represents a potential treatment option for patients with Cancercancer with these BRAF deletions , or other atypical BRAF mutations where BRAF functions as a dimer .
26732495
BACKGROUND : The immune system has important roles in Cancertumor development and outcomes after cancer treatment .
26732495
BACKGROUND : The immune system has important roles in tumor development and outcomes after Cancercancer treatment .
26732495
We evaluated whether single-nucleotide polymorphisms ( SNPs ) in the gene encoding Cancercasitas B-lineage lymphoma b protein ( Cbl-b ) , an E3 ubiquitin ligase that maintains immune tolerance by negatively regulating T-cell activation and function , were associated with outcomes after treatment of non-small-cell lung cancer ( NSCLC ) .
26732495
We evaluated whether single-nucleotide polymorphisms ( SNPs ) in the gene encoding casitas B-lineage lymphoma b protein ( Cbl-b ) , an E3 ubiquitin ligase that maintains immune tolerance by negatively regulating T-cell activation and function , were associated with outcomes after treatment of Cancernon-small-cell lung cancer ( NSCLC ) .
26732495
We evaluated associations between these SNPs and local recurrence-free survival , distant metastasis-free survival , overall survival , and AdverseOutcomerisk of radiation pneumonitis ( RP ) .
26732495
We evaluated associations between these SNPs and local recurrence-free survival , distant metastasis-free survival , overall survival , and risk of Diseaseradiation pneumonitis ( RP ) .
26732495
Patients with these genotypes were also at greater AdverseOutcomerisk of developing grade 3 or higher RP than were patients with GG genotypes in an adjusted Cox proportional hazard model .
26732495
CONCLUSION : This is the first report that rs2305035 genotypes in CBLB were associated with clinical and RP AdverseOutcomerisk among patients with NSCLC treated with definitive radiotherapy .
26739882
KRAS gain-of-function mutations occur in approximately 30 % of all Cancerhuman cancers .
26739882
Despite more than 30 years of KRAS focused research and development efforts , no targeted therapy has been discovered for Cancercancers with KRAS mutations .
26740259
OBJECTIVE : AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival ( PFS ) in patients with Cancerovarian cancer whose disease had not progressed after first-line therapy .
26740259
OBJECTIVE : AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival ( PFS ) in patients with ovarian cancer whose Diseasedisease had not progressed after first-line therapy .
26740259
BRCA1/2 mutation status might be added as strata in future trials in Cancerprimary ovarian cancer .
26745678
Tyrosine kinase inhibitors ( TKIs ) targeting the epidermal growth factor receptor ( EGFR ) have shown promising clinical efficacy in Cancernon squamous non small cell lung cancer ( NSCLC ) ; however , resistance is frequently observed in malignant cells , operating through a mechanism that remains largely unknown .
26745678
TOPK dictates the responsiveness of Cancerlung cancers to the EGFR targeted TKI gefitinib through the transcription factor AP-1 component c-Jun .
26745678
TOPK silencing sensitizes CancerEGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models .
26745678
TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in Cancerpreclinical lung adenocarcinoma xenograft models .
26745678
These findings represent a novel mechanism of Cancerlung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target : TOPK targeted therapy may synergize with EGFR targeted therapy in lung cancers .
26745678
These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target : TOPK targeted therapy may synergize with EGFR targeted therapy in Cancerlung cancers .
26751376
The gene is located at 9p21 , a chromosome region often deleted in Cancerbreast carcinomas , similar to CDKN2A , a recognized tumor suppressor gene .
26751376
Several research groups have shown that MTAP acts as a tumor suppressor , and some therapeutic approaches were proposed based on a Cancertumors ' MTAP status .
26751376
We analyzed MTAP and CDKN2A gene ( RT-qPCR ) and protein ( western blotting ) expression in seven Cancerbreast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer .
26751376
We analyzed MTAP and CDKN2A gene ( RT-qPCR ) and protein ( western blotting ) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to Cancerbreast cancer .
26751376
MTAP expression was also evaluated in two groups of samples from Cancerbreast cancer patients , fresh tumors and paired normal breast tissue , and from formalin fixed paraffin embedded ( FFPE ) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors ( TNBC ) .
26751376
MTAP expression was also evaluated in two groups of samples from breast cancer patients , Cancerfresh tumors and paired normal breast tissue , and from formalin fixed paraffin embedded ( FFPE ) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors ( TNBC ) .
26751376
MTAP expression was also evaluated in two groups of samples from breast cancer patients , fresh tumors and paired normal breast tissue , and from formalin fixed paraffin embedded ( FFPE ) Cancercore breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors ( TNBC ) .
26751376
MTAP expression was also evaluated in two groups of samples from breast cancer patients , fresh tumors and paired normal breast tissue , and from formalin fixed paraffin embedded ( FFPE ) core breast cancer samples diagnosed as CancerLuminal-A tumors and triple negative breast tumors ( TNBC ) .
26751376
MTAP expression was also evaluated in two groups of samples from breast cancer patients , fresh tumors and paired normal breast tissue , and from formalin fixed paraffin embedded ( FFPE ) core breast cancer samples diagnosed as Luminal-A tumors and Cancertriple negative breast tumors ( TNBC ) .
26751376
The difference of MTAP expression between Cancerfresh tumors and normal tissues was not statistically significant .
26751376
However , MTAP expression was significantly higher in CancerLuminal-A breast tumors than in TNBC , suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC .
26751376
However , MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC , suggesting the lack of expression in more Canceraggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC .
26765760
Telomerase reverse transcriptase ( TERT ) has received a great deal of attention in recent years for its role as a prognostic and predictive molecular marker of Cancerglioma .
26765760
A bibliography search using EMBASE and MEDLINE was performed to identify potentially relevant articles and conference abstracts that investigated TERT mutations in Cancerglioma .
26765760
Pooled estimates of the AdverseOutcomerelative risks ( RR ) , 95 % confidence intervals ( 95 % CI ) , hazard ratios ( HR ) and frequency were calculated .
26765760
TERT mutations occurred frequently in Cancerglioblastoma ( 69 % ) and oligodendrogliomas ( 72 % ) but were less frequent in astrocytomas ( 24 % ) and oligoastrocytomas ( 38 % ) .
26765760
TERT mutations occurred frequently in glioblastoma ( 69 % ) and Canceroligodendrogliomas ( 72 % ) but were less frequent in astrocytomas ( 24 % ) and oligoastrocytomas ( 38 % ) .
26765760
TERT mutations occurred frequently in glioblastoma ( 69 % ) and oligodendrogliomas ( 72 % ) but were less frequent in Cancerastrocytomas ( 24 % ) and oligoastrocytomas ( 38 % ) .
26765760
TERT mutations occurred frequently in glioblastoma ( 69 % ) and oligodendrogliomas ( 72 % ) but were less frequent in astrocytomas ( 24 % ) and Canceroligoastrocytomas ( 38 % ) .
26765760
The HR for Cancerglioma patients with TERT mutations versus wild type TERT was 1.63 ( 95 % CI 1.35-1 .98 ) .
26765760
TERT polymorphisms were associated with an AdverseOutcomeincreased risk of glioma compared to controls ( RR = 1.28 , 95 % CI 1.23-1 .33 ) .
26765760
TERT polymorphisms were associated with an increased risk of Cancerglioma compared to controls ( RR = 1.28 , 95 % CI 1.23-1 .33 ) .
26765760
Our study shows that the TERT gene is a valuable prognostic and predictive biomarker of Cancerglioma , and TERT gene polymorphisms are significantly associated with an increased risk of glioma .
26765760
Our study shows that the TERT gene is a valuable prognostic and predictive biomarker of glioma , and TERT gene polymorphisms are significantly associated with an AdverseOutcomeincreased risk of glioma .
26765760
Our study shows that the TERT gene is a valuable prognostic and predictive biomarker of glioma , and TERT gene polymorphisms are significantly associated with an increased risk of Cancerglioma .
26771088
Treatment success in patients with Diseaseacute myeloid leukaemia ( AML ) is heterogeneous .
26771088
Here , we studied the impact of TP53 mutations on the outcome of AML patients with adverse AdverseOutcomecytogenetic risk treated with allogeneic haematopoietic stem cell transplantation ( HSCT ) .
26771872
BACKGROUND : Expression of programmed cell death-ligand 1 ( PD-L1 ) is known to be a mechanism whereby Cancercancer can escape immune surveillance , but little is known about factors predictive of efficacy in patients with locally advanced non small cell lung cancer ( NSCLC ) .
26771872
BACKGROUND : Expression of programmed cell death-ligand 1 ( PD-L1 ) is known to be a mechanism whereby cancer can escape immune surveillance , but little is known about factors predictive of efficacy in patients with locally Canceradvanced non small cell lung cancer ( NSCLC ) .
26771872
We investigated the predictive relevance of PD-L1 expression and CancerCD8+ tumour infiltrating lymphocytes ( TILs ) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy ( CCRT ) .
26773740
In particular , exon 18 G719 mutations , exon 19 K757R and E746G mutations , the exon 20 S768I mutation , and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment , whereas exon 18 S720I showed a particularly AdverseOutcomepoor outcome .
26773740
More research is needed to create a central database such as the My CancerCancer Genome database of rare mutations to definitively confirm whether these mutations are activating , resistant , or neutral .
26775591
The emergence of acquired Canceranaplastic lymphoma kinase ( ALK ) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK positive ( ALK+ ) non small cell lung cancer ( NSCLC ) patients .
26775591
The emergence of acquired anaplastic lymphoma kinase ( ALK ) resistant mutations is a common molecular mechanism underpinning Diseasedisease progression during crizotinib treatment of ALK positive ( ALK+ ) non small cell lung cancer ( NSCLC ) patients .
26775591
The emergence of acquired anaplastic lymphoma kinase ( ALK ) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK positive ( ALK+ ) Cancernon small cell lung cancer ( NSCLC ) patients .
26775591
Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient ( EML4-ALK variant 3a/b ) who developed Diseaseslow disease progression after a durable response to crizotinib .
26778701
A mutant form of epidermal growth factor receptor ( EGFR ) , EGFRvIII , is common in Cancerglioblastoma ( GBM ) and confers enhanced tumorigenic activity and drug resistance .
26778701
CancerHuman glioma U87MG or LNZ308 cells overexpressing either wild-type ( wt ) EGFR or EGFRvIII were treated with nimotuzumab , temozolomide , or both .
26778701
Correspondingly , antitumor effects , growth suppression and survival elongation , were more significant in mice bearing either subcutaneous or Cancerintracerebral tumor expressing EGFRvIII than in those expressing wtEGFR .
26778701
The Cancerpost-treatment recurrent brain tumors exhibited a decrease in expression of the mismatch repair ( MMR ) proteins , MSH6 and MLH1 , but their methylated MGMT status did not changed .
26786851
ALK receptor tyrosine kinase has been shown to be a therapeutic target in Cancerneuroblastoma .
26786851
Germline ALK activating mutations are responsible for the majority of Cancerhereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB .
26786851
Crizotinib , a first-line therapy in the treatment of Canceradvanced non small cell lung cancer ( NSCLC ) harboring ALK rearrangements , demonstrates striking efficacy against ALK rearranged NB .
26786851
AZD3463 also exhibited significant therapeutic efficacy on the growth of the CancerNB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models .
26787751
EXPERIMENTAL DESIGN : Once-daily oral apitolisib was administered to patients with Cancersolid tumors for days 1 to 21 or 1 to 28 of 28-day cycles .
26787751
The Diseasecommonest > = G3 toxicities related to apitolisib at the recommended phase 2 dose ( RP2D ) at 40 mg once daily included hyperglycemia ( 18 % ) , rash ( 14 % ) , liver dysfunction ( 12 % ) , diarrhea ( 10 % ) , pneumonitis ( 8 % ) , mucosal inflammation ( 6 % ) , and fatigue ( 4 % ) .
26787751
The commonest > = G3 toxicities related to apitolisib at the recommended phase 2 dose ( RP2D ) at 40 mg once daily included Diseasehyperglycemia ( 18 % ) , rash ( 14 % ) , liver dysfunction ( 12 % ) , diarrhea ( 10 % ) , pneumonitis ( 8 % ) , mucosal inflammation ( 6 % ) , and fatigue ( 4 % ) .
26787751
The commonest > = G3 toxicities related to apitolisib at the recommended phase 2 dose ( RP2D ) at 40 mg once daily included hyperglycemia ( 18 % ) , rash ( 14 % ) , liver dysfunction ( 12 % ) , diarrhea ( 10 % ) , Diseasepneumonitis ( 8 % ) , mucosal inflammation ( 6 % ) , and fatigue ( 4 % ) .
26787751
The commonest > = G3 toxicities related to apitolisib at the recommended phase 2 dose ( RP2D ) at 40 mg once daily included hyperglycemia ( 18 % ) , rash ( 14 % ) , liver dysfunction ( 12 % ) , diarrhea ( 10 % ) , pneumonitis ( 8 % ) , Diseasemucosal inflammation ( 6 % ) , and fatigue ( 4 % ) .
26787751
Dose limiting Diseasetoxicities ( 1 patient each ) were G4 fasting hyperglycemia at 40 mg ( 21/28 schedule ) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg ( 21/28 schedule ) .
26787751
Dose limiting toxicities ( 1 patient each ) were DiseaseG4 fasting hyperglycemia at 40 mg ( 21/28 schedule ) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg ( 21/28 schedule ) .
26787751
Dose limiting toxicities ( 1 patient each ) were G4 fasting hyperglycemia at 40 mg ( 21/28 schedule ) and G3 maculopapular rash and DiseaseG3 fasting hyperglycemia at 70 mg ( 21/28 schedule ) .
26787751
Evidence of single-agent activity included 10 RECIST partial responses ( PR ; confirmed for Cancerperitoneal mesothelioma , PIK3CA mutant head-and-neck cancer , and three pleural mesotheliomas ) .
26787751
Evidence of single-agent activity included 10 RECIST partial responses ( PR ; confirmed for peritoneal mesothelioma , CancerPIK3CA mutant head-and-neck cancer , and three pleural mesotheliomas ) .
26787751
Evidence of single-agent activity included 10 RECIST partial responses ( PR ; confirmed for peritoneal mesothelioma , PIK3CA mutant head-and-neck cancer , and three Cancerpleural mesotheliomas ) .
26787751
The RP2D was 40 mg once-daily 28/28 schedule ; Diseasesevere on-target toxicities were apparent at > = 40 mg , particularly pneumonitis .
26787751
The RP2D was 40 mg once-daily 28/28 schedule ; severe on-target toxicities were apparent at > = 40 mg , particularly Diseasepneumonitis .
26787751
Apitolisib was reasonably tolerated at 30 mg , the selected dose for Cancerpleural mesothelioma patients given limited respiratory reserve .
26789727
BACKGROUND : Despite the molecular heterogeneity of Cancerstandard-risk acute myeloid leukemia ( AML ) , treatment decisions are based on a limited number of molecular genetic markers and morphology based assessment of remission .
26789727
Sensitive detection of a Cancerleukemia specific marker ( e.g. , a mutation in the gene encoding nucleophosmin [ NPM1 ] ) could improve prognostication by identifying submicroscopic disease during remission .
26789727
Sensitive detection of a leukemia specific marker ( e.g. , a mutation in the gene encoding nucleophosmin [ NPM1 ] ) could improve prognostication by identifying Diseasesubmicroscopic disease during remission .
26789727
METHODS : We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect Diseaseminimal residual disease in 2569 samples obtained from 346 patients with NPM1 mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial .
26789727
Persistence of NPM1 mutated transcripts in blood was present in 15 % of the patients after the second chemotherapy cycle and was associated with a greater AdverseOutcomerisk of relapse after 3 years of follow-up than was an absence of such transcripts ( 82 % vs. 30 % ; hazard ratio , 4.80 ; 95 % confidence interval [ CI ] , 2.95 to 7.80 ; P < 0.001 ) and a lower rate of survival ( 24 % vs. 75 % ; hazard ratio for death , 4.38 ; 95 % CI , 2.57 to 7.47 ; P < 0.001 ) .
26789727
The presence of Diseaseminimal residual disease was the only independent prognostic factor for death in multivariate analysis ( hazard ratio , 4.84 ; 95 % CI , 2.57 to 9.15 ; P < 0.001 ) .
26789727
On sequential monitoring of Diseaseminimal residual disease , relapse was reliably predicted by a rising level of NPM1 mutated transcripts .
26789727
Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy , NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of Diseasedisease status .
26789727
CONCLUSIONS : The presence of Diseaseminimal residual disease , as determined by quantitation of NPM1 mutated transcripts , provided powerful prognostic information independent of other risk factors .
26789727
CONCLUSIONS : The presence of minimal residual disease , as determined by quantitation of NPM1 mutated transcripts , provided powerful prognostic information independent of AdverseOutcomeother risk factors .
26789870
Background The identification of high-risk stage II Cancercolon cancers is key to the selection of patients who require adjuvant treatment after surgery .
26789870
With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III Cancercolon cancer , the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy .
26789870
A group of 87 of 2115 Cancertumor samples ( 4.1 % ) lacked CDX2 expression .
26789870
In the discovery data set , which included 466 patients , the rate of 5-year disease-free survival was lower among the 32 patients ( 6.9 % ) with CancerCDX2 negative colon cancers than among the 434 ( 93.1 % ) with CDX2 positive colon cancers ( hazard ratio for disease recurrence , 3.44 ; 95 % confidence interval [ CI ] , 1.60 to 7.38 ; P = 0.002 ) .
26789870
In the discovery data set , which included 466 patients , the rate of 5-year disease-free survival was lower among the 32 patients ( 6.9 % ) with CDX2 negative colon cancers than among the 434 ( 93.1 % ) with CancerCDX2 positive colon cancers ( hazard ratio for disease recurrence , 3.44 ; 95 % confidence interval [ CI ] , 1.60 to 7.38 ; P = 0.002 ) .
26789870
In the discovery data set , which included 466 patients , the rate of 5-year disease-free survival was lower among the 32 patients ( 6.9 % ) with CDX2 negative colon cancers than among the 434 ( 93.1 % ) with CDX2 positive colon cancers ( hazard ratio for Diseasedisease recurrence , 3.44 ; 95 % confidence interval [ CI ] , 1.60 to 7.38 ; P = 0.002 ) .
26789870
In the validation data set , which included 314 patients , the rate of 5-year disease-free survival was lower among the 38 patients ( 12.1 % ) with CancerCDX2 protein negative colon cancers than among the 276 ( 87.9 % ) with CDX2 protein positive colon cancers ( hazard ratio , 2.42 ; 95 % CI , 1.36 to 4.29 ; P = 0.003 ) .
26789870
In the validation data set , which included 314 patients , the rate of 5-year disease-free survival was lower among the 38 patients ( 12.1 % ) with CDX2 protein negative colon cancers than among the 276 ( 87.9 % ) with CancerCDX2 protein positive colon cancers ( hazard ratio , 2.42 ; 95 % CI , 1.36 to 4.29 ; P = 0.003 ) .
26789870
In both these groups , these findings were independent of the patient 's age , sex , and Cancertumor stage and grade .
26789870
Among patients with stage II Cancercancer , the difference in 5-year disease-free survival was significant both in the discovery data set ( 49 % among 15 patients with CDX2 negative tumors vs. 87 % among 191 patients with CDX2 positive tumors , P = 0.003 ) and in the validation data set ( 51 % among 15 patients with CDX2 negative tumors vs. 80 % among 106 patients with CDX2 positive tumors , P = 0.004 ) .
26789870
Among patients with stage II cancer , the difference in 5-year disease-free survival was significant both in the discovery data set ( 49 % among 15 patients with CancerCDX2 negative tumors vs. 87 % among 191 patients with CDX2 positive tumors , P = 0.003 ) and in the validation data set ( 51 % among 15 patients with CDX2 negative tumors vs. 80 % among 106 patients with CDX2 positive tumors , P = 0.004 ) .
26789870
Among patients with stage II cancer , the difference in 5-year disease-free survival was significant both in the discovery data set ( 49 % among 15 patients with CDX2 negative tumors vs. 87 % among 191 patients with CancerCDX2 positive tumors , P = 0.003 ) and in the validation data set ( 51 % among 15 patients with CDX2 negative tumors vs. 80 % among 106 patients with CDX2 positive tumors , P = 0.004 ) .
26789870
Among patients with stage II cancer , the difference in 5-year disease-free survival was significant both in the discovery data set ( 49 % among 15 patients with CDX2 negative tumors vs. 87 % among 191 patients with CDX2 positive tumors , P = 0.003 ) and in the validation data set ( 51 % among 15 patients with CancerCDX2 negative tumors vs. 80 % among 106 patients with CDX2 positive tumors , P = 0.004 ) .
26789870
Among patients with stage II cancer , the difference in 5-year disease-free survival was significant both in the discovery data set ( 49 % among 15 patients with CDX2 negative tumors vs. 87 % among 191 patients with CDX2 positive tumors , P = 0.003 ) and in the validation data set ( 51 % among 15 patients with CDX2 negative tumors vs. 80 % among 106 patients with CancerCDX2 positive tumors , P = 0.004 ) .
26789870
In a pooled database of all patient cohorts , the rate of 5-year disease-free survival was higher among 23 patients with stage II CancerCDX2 negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy ( 91 % vs. 56 % , P = 0.006 ) .
26789870
Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II Cancercolon cancer who appeared to benefit from adjuvant chemotherapy .
26802149
BACKGROUND : Genomic studies in Cancersmall-cell lung cancer ( SCLC ) lag far behind those carried out in nonsmall-cell lung cancer ( NSCLC ) .
26802149
BACKGROUND : Genomic studies in small-cell lung cancer ( SCLC ) lag far behind those carried out in Cancernonsmall-cell lung cancer ( NSCLC ) .
26802149
To date , most SCLC studies have evaluated patients with surgically Diseaseresectable disease .
26802149
Here we sought to evaluate the genomic mutation spectrum of ' every-day ' CancerSCLC patient tumors with extensive stage disease ( ES-SCLC ) and to correlate mutations with the main clinical outcomes of response to chemotherapy , progression-free ( PFS ) and overall ( OS ) survival .
26802149
Here we sought to evaluate the genomic mutation spectrum of ' every-day ' SCLC patient tumors with Diseaseextensive stage disease ( ES-SCLC ) and to correlate mutations with the main clinical outcomes of response to chemotherapy , progression-free ( PFS ) and overall ( OS ) survival .
26802149
PATIENTS AND METHODS : A total of 50 CancerSCLC patient tumors were examined in this study ; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients .
26802149
RB1 protein expression was detected by either western blotting of cultured cell lysates or immunohistochemistry of Cancertumor specimens .
26802149
RESULTS : In all , 39 patients had ES-SCLC ; 15 patients had either primary refractory and Diseaseresistant disease and 21 patients had sensitive disease .
26802149
RESULTS : In all , 39 patients had ES-SCLC ; 15 patients had either primary refractory and resistant disease and 21 patients had Diseasesensitive disease .
26802149
Interestingly , ~ 25 % of SCLC cell lines and Cancertumor specimens expressed RB1 protein , possibly representing the subgroup with wild-type RB1 .
26802149
CONCLUSIONS : We found that CancerSCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy .
26807188
BACKGROUND : Neoadjuvant concurrent chemoradiotherapy ( CCRT ) followed by surgery is the mainstay of treatment for locally Canceradvanced rectal cancer .
26807188
Several heparin binding associated proteins have been reported to play a critical role in Cancercancer progression .
26807188
However , the clinical relevancies of such proteins and their associations with CCRT response in Cancerrectal cancer have not yet to be fully elucidated .
26807188
METHODS : The analysis of a public transcriptome of Cancerrectal cancer indicated that thrombospondin 2 ( THBS2 ) is a predictive factor for CCRT response .
26807188
Immunohistochemical analyses were conducted to evaluate the expression of THBS2 in pretreatment biopsy specimens from Cancerrectal cancer patients without distant metastasis .
26807188
Immunohistochemical analyses were conducted to evaluate the expression of THBS2 in pretreatment biopsy specimens from rectal cancer patients without Cancerdistant metastasis .
26807188
RESULTS : Low expression of THBS2 was significantly associated with Canceradvanced pretreatment tumor ( P < 0.001 ) and nodal status ( P = 0.004 ) , post-treatment tumor ( P < 0.001 ) and nodal status ( P < 0.001 ) , increased vascular invasion ( P = 0.003 ) , increased perineural invasion ( P = 0.023 ) and inferior tumor regression grade ( P = 0.015 ) .
26807188
RESULTS : Low expression of THBS2 was significantly associated with advanced pretreatment tumor ( P < 0.001 ) and nodal status ( P = 0.004 ) , Cancerpost-treatment tumor ( P < 0.001 ) and nodal status ( P < 0.001 ) , increased vascular invasion ( P = 0.003 ) , increased perineural invasion ( P = 0.023 ) and inferior tumor regression grade ( P = 0.015 ) .
26807188
RESULTS : Low expression of THBS2 was significantly associated with advanced pretreatment tumor ( P < 0.001 ) and nodal status ( P = 0.004 ) , post-treatment tumor ( P < 0.001 ) and nodal status ( P < 0.001 ) , increased vascular invasion ( P = 0.003 ) , increased perineural invasion ( P = 0.023 ) and Cancerinferior tumor regression grade ( P = 0.015 ) .
26807188
CONCLUSION : Low THBS2 expression was correlated with Diseaseadvanced disease status and low tumor regression after preoperative CCRT and that it acted as an independent negative prognostic factor in rectal cancer .
26807188
CONCLUSION : Low THBS2 expression was correlated with advanced disease status and Cancerlow tumor regression after preoperative CCRT and that it acted as an independent negative prognostic factor in rectal cancer .
26807188
CONCLUSION : Low THBS2 expression was correlated with advanced disease status and low tumor regression after preoperative CCRT and that it acted as an independent negative prognostic factor in Cancerrectal cancer .
26807188
THBS2 may represent a predictive biomarker for CCRT response in Cancerrectal cancer .
26811533
PURPOSE : We examined the prognostic and predictive value of serum human epidermal growth factor 2 ( HER2 ) extracellular domain ( sHER2 ) in patients with Canceradvanced breast cancer treated with lapatinib using data from three randomized trials .
26812186
BACKGROUND : CancerMetastatic colorectal cancer ( mCRC ) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies ( mAbs ) .
26812186
BACKGROUND : Metastatic colorectal cancer ( mCRC ) Cancertumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies ( mAbs ) .
26812186
However , observational evidence has led to speculation that mCRC patients with KRAS G13D mutant ( MT ) Cancertumours may derive a benefit from treatment with anti-EGFR mAbs .
26812186
METHODS : We conducted a systematic review and meta-analysis of randomized controlled trials ( RCTs ) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between Cancertumours harbouring a KRAS G13D mutation ( KRAS G13D ) and KRAS mutations other than G13D ( other KRAS MT ) .
26812186
In contrast , the hazard ratio for KRAS wild-type ( WT ) Cancertumours was 0.85 ( 95 % CI ; 0.76 , 0.95 ) .
26812186
Again , the test for interaction ( p = 0.46 ) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. CONCLUSION : This meta-analysis demonstrates no significant difference between KRAS G13D and Cancerother KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC .
26821351
CancerHigh-risk neuroblastoma remains lethal in about 50 % of patients despite multimodal treatment .
26821351
However , few inhibitors for the potential treatment for CancerNRAS mutant neuroblastoma have been investigated so far .
26821351
In this in-vitro study , we show that MEK inhibitors AZD6244 , MEK162 and PD0325901 block cell growth in CancerNRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines .
26821351
We found that Everolimus alone induced apoptosis in CancerNRAS mutant neuroblastoma .
26821351
Taken together , our results show that CancerNRAS mutant neuroblastoma can be targeted by clinically available Everolimus alone or in combination with MEK inhibitors which could impact future clinical studies .
26822383
Anti-PD-1 therapy yields objective clinical responses in 30-40 % of Canceradvanced melanoma patients .
26822383
We hypothesize that MHC-I/II expression is required for Cancertumour antigen presentation and may predict anti-PD-1 therapy response .
26822383
In this study , across 60 Cancermelanoma cell lines , we find bimodal expression patterns of MHC-II , while MHC-I expression was ubiquitous .
26822383
A unique subset of Cancermelanomas are capable of expressing MHC-II under basal or IFNgamma stimulated conditions .
26822383
In two independent cohorts of Canceranti-PD-1-treated melanoma patients , MHC-II positivity on tumour cells is associated with therapeutic response , progression-free and overall survival , as well as CD4 ( + ) and CD8 ( + ) tumour infiltrate .
26822383
In two independent cohorts of anti-PD-1-treated melanoma patients , MHC-II positivity on Cancertumour cells is associated with therapeutic response , progression-free and overall survival , as well as CD4 ( + ) and CD8 ( + ) tumour infiltrate .
26822383
In two independent cohorts of anti-PD-1-treated melanoma patients , MHC-II positivity on tumour cells is associated with therapeutic response , progression-free and overall survival , as well as CD4 ( + ) and CD8 ( + ) Cancertumour infiltrate .
26822383
MHC-II ( + ) Cancertumours can be identified by melanoma specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection .
26822383
MHC-II ( + ) tumours can be identified by Cancermelanoma specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection .
26822398
BACKGROUND : Trastuzumab resistance is a key therapeutic challenge in Cancermetastatic breast cancer .
26822398
LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with CancerHER2 positive metastatic breast cancer .
26822398
We enrolled female patients with HER2 overexpressing Cancermetastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab .
26822398
We enrolled female patients with HER2 overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of Diseasemetastatic disease with trastuzumab .
26822398
The most common drug related adverse events of grade 3 or higher were Diseaseneutropenia ( 190 [ 56 % ] of 337 patients in the afatinib group vs 102 [ 60 % ] of 169 patients in the trastuzumab group ) , leucopenia ( 64 [ 19 % ] vs 34 [ 20 % ] ) , and diarrhoea ( 60 [ 18 % ] vs none ) .
26822398
The most common drug related adverse events of grade 3 or higher were neutropenia ( 190 [ 56 % ] of 337 patients in the afatinib group vs 102 [ 60 % ] of 169 patients in the trastuzumab group ) , Diseaseleucopenia ( 64 [ 19 % ] vs 34 [ 20 % ] ) , and diarrhoea ( 60 [ 18 % ] vs none ) .
26822398
INTERPRETATION : Trastuzumab based therapy remains the treatment of choice for patients with CancerHER2 positive metastatic breast cancer who had progressed on trastuzumab .
26837699
Genomic studies have revealed the complex clonal heterogeneity of Cancerchronic lymphocytic leukemia ( CLL ) .
26837699
The acquisition and selection of genomic aberrations may be critical to understanding the progression of this Diseasedisease .
26837699
These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the Diseasedisease may be relevant for the management of CLL patients .
26838030
Recent whole-genome sequencing studies have identified that genetic alterations of stag2 are common in Cancerbladder cancer ( BC ) .
26838030
We used immunohistochemistry assay to determine STAG2 protein expression in Cancertumor tissues from 125 BC patients .
26838030
Univariable and multivariable analyses were performed to identify predictors for recurrence-free survival ( RFS ) and Cancercancer specific survival ( CSS ) .
26838030
STAG2 expression was detected in 79.2 % of BC tissues , and 20.8 % of the Cancertumor tissues had a complete loss of STAG2 protein expression .
26838030
This STAG2 negative result was associated with a Cancerlower tumor histological grade with P = 0.009 .
26838030
The log-rank analysis revealed that the complete loss of STAG2 expression was associated with a lower AdverseOutcomerisk of recurrence ( P = 0.023 ) and a diminished risk of death ( P = 0.034 ) , especially in the subgroup of muscle-invasive BC ( P = 0.043 for RFS and P = 0.087 for CSS ) .
26838030
The log-rank analysis revealed that the complete loss of STAG2 expression was associated with a lower risk of recurrence ( P = 0.023 ) and a AdverseOutcomediminished risk of death ( P = 0.034 ) , especially in the subgroup of muscle-invasive BC ( P = 0.043 for RFS and P = 0.087 for CSS ) .
26867820
Importance : RAS wild-type ( wt ) status is necessary but not sufficient for response to anti-epidermal growth factor receptor ( EGFR ) agents in Canceradvanced colorectal cancer ( aCRC ) .
26867820
Objective : To examine a novel ligand model in a randomized clinical trial of panitumumab , irinotecan , and ciclosporin in Cancercolorectal cancer ( PICCOLO ) with with the a priori hypothesis that high tumor expression of either AREG or EREG would predict panitumumab therapy benefit in RAS-wt patients ; and low expression , lack of efficacy .
26867820
Objective : To examine a novel ligand model in a randomized clinical trial of panitumumab , irinotecan , and ciclosporin in colorectal cancer ( PICCOLO ) with with the a priori hypothesis that Cancerhigh tumor expression of either AREG or EREG would predict panitumumab therapy benefit in RAS-wt patients ; and low expression , lack of efficacy .
26867820
A predefined dichotomous model classified Cancertumors as " high expressor " ( either EREG or AREG in top tertile for messenger RNA level ) or " low expressor " ( neither EREG nor AREG in top tertile ) .
26867820
Expression of AREG and EREG and RAS and BRAF mutations were assessed in Cancerarchival tumor tissue .
26867820
Results : Of the 696 PICCOLO trial patients in the irinotecan-vs-irinotecan with panitumumab randomization , 331 had Cancersufficient tumor tissue available and measurement of ligand expression was successful in 323 .
26872370
Hypoxia inducible factor-1 alpha ( HIF-1alpha ) is over-expressed in Cancermany cancers including pancreatic ductal adenocarcinoma ( PDAC ) and correlated with poor prognosis .
26872370
Hypoxia inducible factor-1 alpha ( HIF-1alpha ) is over-expressed in many cancers including Cancerpancreatic ductal adenocarcinoma ( PDAC ) and correlated with poor prognosis .
26872370
Hypoxia inducible factor-1 alpha ( HIF-1alpha ) is over-expressed in many cancers including pancreatic ductal adenocarcinoma ( PDAC ) and correlated with AdverseOutcomepoor prognosis .
26872370
We aim to determine the effect of germline genetic variants on the regulation of the homeostasis of the miRNA gene regulatory loop in HIF1A gene and PDAC AdverseOutcomerisk .
26872370
The CC genotype SNP HIF1A is significantly correlated with PDAC AdverseOutcomerisk ( OR = 1.719 , 95 % CI : 1.293-2 .286 ) and shorter overall survival ( OS , P < 0.0001 ) compared with the CT/TT alleles group .
26872370
Taken together , our study demonstrates that host genetic variants could disturb the regulation of the miR-199a and HIF1A regulatory loop and alter PDAC AdverseOutcomerisk and poor prognosis .
26872370
Taken together , our study demonstrates that host genetic variants could disturb the regulation of the miR-199a and HIF1A regulatory loop and alter PDAC risk and AdverseOutcomepoor prognosis .
26872370
In conclusion , the rs2057482-CC genotype increases the susceptibility to PDAC and associated with Cancercancer progression .
26874901
BACKGROUND : Neratinib , an irreversible tyrosine kinase inhibitor of HER1 , HER2 , and HER4 , has clinical activity in patients with CancerHER2 positive metastatic breast cancer .
26874901
We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab based adjuvant therapy in patients with Cancerearly-stage HER2 positive breast cancer .
26874901
Eligible women ( aged > = 18 years , or > = 20 years in Japan ) had stage 1-3 CancerHER2 positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation .
26874901
Inclusion criteria were amended on Feb 25 , 2010 , to include patients with stage 2-3 CancerHER2 positive breast cancer who had completed trastuzumab therapy up to 1 year previously .
26874901
Seven ( < 1 % ) deaths ( four patients in the neratinib group and three patients in the placebo group ) unrelated to Diseasedisease progression occurred after study drug discontinuation .
26874901
The causes of death in the neratinib group were unknown ( n = 2 ) , a Cancersecond primary brain tumour ( n = 1 ) , and acute myeloid leukaemia ( n = 1 ) , and in the placebo group were a brain haemorrhage ( n = 1 ) , myocardial infarction ( n = 1 ) , and gastric cancer ( n = 1 ) .
26874901
The causes of death in the neratinib group were unknown ( n = 2 ) , a second primary brain tumour ( n = 1 ) , and Diseaseacute myeloid leukaemia ( n = 1 ) , and in the placebo group were a brain haemorrhage ( n = 1 ) , myocardial infarction ( n = 1 ) , and gastric cancer ( n = 1 ) .
26874901
The causes of death in the neratinib group were unknown ( n = 2 ) , a second primary brain tumour ( n = 1 ) , and acute myeloid leukaemia ( n = 1 ) , and in the placebo group were a brain haemorrhage ( n = 1 ) , myocardial infarction ( n = 1 ) , and Cancergastric cancer ( n = 1 ) .
26874901
INTERPRETATION : Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab based adjuvant therapy to women with CancerHER2 positive breast cancer .
26874901
Longer follow-up is needed to ensure that the improvement in Cancerbreast cancer outcome is maintained .
26881434
Activating KRAS mutations are found in approximately 20 % of Cancerhuman cancers but no RAS directed therapies are currently available .
26881434
This was discovered using parallel siRNA screens in KRAS mutant and Cancerwild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models .
26881434
This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and Cancerpancreatic tumour cell models .
26881434
This established that the KRAS and CDK1 synthetic lethality applies in Cancertumour cells with either amino acid position 12 ( p.G12V , pG12D , p.G12S ) or amino acid position 13 ( p.G13D ) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor .
26883990
Despite compelling antitumour activity of antibodies targeting the programmed death 1 ( PD-1 ) : programmed death ligand 1 ( PD-L1 ) immune checkpoint in Cancerlung cancer , resistance to these therapies has increasingly been observed .
26883990
In this study , to elucidate mechanisms of adaptive resistance , we analyse the Cancertumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma .
26883990
In this study , to elucidate mechanisms of adaptive resistance , we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of Cancerlung adenocarcinoma .
26883990
In Cancertumours progressing following response to anti-PD-1 therapy , we observe upregulation of alternative immune checkpoints , notably T-cell immunoglobulin mucin-3 ( TIM-3 ) , in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade .
26884591
BACKGROUND : CancerMammary analogue secretory carcinoma ( MASC ) is a recently described pathologic entity .
26884591
We report the case of a patient with an initial diagnosis of Cancersalivary acinic cell carcinoma later reclassified as MASC after next generation sequencing revealed an ETV6-NTRK3 fusion .
26884591
CONCLUSIONS : This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3 rearranged Cancercancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies ( NCT02097810 ) .
26884591
CONCLUSIONS : This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3 rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for Cancerrare malignancies ( NCT02097810 ) .
26888827
PURPOSE : Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with Cancermetastatic colorectal cancer ( MCRC ) .
26888827
However , patients ultimately develop Diseasedisease progression , often driven by acquisition of mutations in the extracellular domain ( ECD ) of EGFR .
26888827
Cell viability and molecular effects of the drugs were assayed in cetuximab resistant cell lines and in Cancertumor xenograft models .
26888827
Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the Cancerpost-cetuximab tumor sample .
26888827
Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004 , which was consistent with an effective suppression of EGFR downstream signaling , translating into profound and Cancersustained tumor regression in the xenograft model .
26888827
As proof-of-principle , a patient with a Cancertumor harboring an EGFR mutation ( G465R ) following cetuximab therapy benefited from Sym004 therapy .
26891277
Fibroblast growth factor homologous factors ( FHFs ) belong to the fibroblast growth factor ( FGF ) superfamily , which plays an important role in Cancerprostate cancer ( PCa ) .
26891277
There was a significant association between high cytoplasmic FGF13 staining and a AdverseOutcomerisk of biochemical recurrence ( BCR ) after RP .
26891277
In contrast , positive nuclear FGF13 staining along with low cytoplasmic FGF13 group showed a decreased BCR AdverseOutcomerisk .
26892177
Paclitaxel frequently serves as the first-line chemotherapeutic agent for Cancercastration resistant prostate cancer ( PCa ) patients .
26892177
Furthermore , in vivo assay of xenograft transplantation confirmed the higher tumorigenicity of DU145-TxR cells , suggesting that these paclitaxel resistant PCa cells possessed Cancerpotent cancer stem cell ( CSC )-like properties and eventually developed paclitaxel-resistance .
26892177
Moreover , we determined by immunohistochemistry that CK18 expression in PCa tissues was inversely correlated with Cancertumor grade in a statistically significant fashion , indicating a potential association of the downregulation of CK18 with tumor aggressiveness .
26892177
Moreover , we determined by immunohistochemistry that CK18 expression in PCa tissues was inversely correlated with tumor grade in a statistically significant fashion , indicating a potential association of the downregulation of CK18 with Cancertumor aggressiveness .
26893365
Eighty SNPs in miRNA binding sites of Cancercancer related genes selected from 18,500 miRNA : target bindings in crosslinking , ligation , and sequencing of hybrids ( CLASH ) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry based genotype assay .
26893365
Notably , ETS2 rs461155A > G was significantly associated with decreased ETS2 mRNA expression in both Cancertumor and paired normal lung tissues ( Ptrend = 4 x 10-7 , and 3 x 10-4 , respectively ) .
26893853
Human enhancer of filamentation 1 ( HEF1 ) , a scaffold protein , is highly expressed in a variety of Cancercancer types and is involved cancer cell growth , migration and invasion .
26893853
Human enhancer of filamentation 1 ( HEF1 ) , a scaffold protein , is highly expressed in a variety of cancer types and is involved Cancercancer cell growth , migration and invasion .
26893853
The prognostic value of HEF1 in Cancerhepatocellular carcinoma ( HCC ) remains to be elucidated .
26893853
In the present study , immunohistochemistry was performed to investigate the protein expression of HEF1 in 123 Cancerhepatocellular carcinoma tissues and their adjacent normal liver tissues .
26893853
High expression of HEF1 correlated with Cancerhigher advanced tumor , node , metastasis ( TNM ) stage and vascular invasion ( P < 0.05 ) .
26893853
High expression of HEF1 correlated with higher advanced tumor , node , Cancermetastasis ( TNM ) stage and vascular invasion ( P < 0.05 ) .
26894380
Cancerous inhibitor of protein phosphatase 2A ( CIP2A ) is an oncoprotein which participates in inhibiting Cancertumor apoptosis in pancreatic cancer cells .
26894380
Cancerous inhibitor of protein phosphatase 2A ( CIP2A ) is an oncoprotein which participates in inhibiting tumor apoptosis in Cancerpancreatic cancer cells .
26894380
Using immunohistochemical staining , we investigated the expression of CIP2A protein in 72 cases of Cancerhuman pancreatic ductal adenocarcinoma ( PDAC ) tissue and 27 cases of adjacent normal pancreatic tissue .
26894380
The positive rate of CIP2A protein expression in Cancerpancreatic cancer tissue was70 .83 % , which was significantly higher than that in adjacent non- cancerous pancreatic tissue ( 11.11 % ) .
26894380
The expression of CIP2A was found to be correlated with TNM stage , but not correlated with age , gender , Cancertumor location , smoking status , alcohol consumption , diabetes , high blood pressure , BMI , tumor size , lymph node metastasis or distant metastases .
26894380
The expression of CIP2A was found to be correlated with TNM stage , but not correlated with age , gender , tumor location , smoking status , alcohol consumption , diabetes , high blood pressure , BMI , Cancertumor size , lymph node metastasis or distant metastases .
26894380
The expression of CIP2A was found to be correlated with TNM stage , but not correlated with age , gender , tumor location , smoking status , alcohol consumption , diabetes , high blood pressure , BMI , tumor size , Cancerlymph node metastasis or distant metastases .
26894380
COX regression analysis indicated that expression of CIP2A was an independent prognostic factor for Cancerpancreatic ductal adenocarcinoma .
26894380
In addition , down-regulation of CIP2A inhibited cell proliferation and increased sensitivity to gemcitabine in Cancerpancreatic cancer cells by decreasing AKT signaling pathway .
26894380
Our results indicated that down-regulation of CIP2A could be a novel therapeutic strategy for Cancerpancreatic cancer .
26894620
CancerAdenocarcinoma accounts for ~ 40 % of lung cancer , equating to ~ 88500 new patients in 2015 , most of who will succumb to this disease , thus , the public health burden is evident .
26894620
Adenocarcinoma accounts for ~ 40 % of Cancerlung cancer , equating to ~ 88500 new patients in 2015 , most of who will succumb to this disease , thus , the public health burden is evident .
26894620
Adenocarcinoma accounts for ~ 40 % of lung cancer , equating to ~ 88500 new patients in 2015 , most of who will succumb to this Diseasedisease , thus , the public health burden is evident .
26894620
Unfortunately , few early biomarkers as well as effective therapies exist , hence the need for novel targets in Cancerlung cancer treatment .
26894620
We previously identified epiregulin ( Ereg ) , an EGF like ligand , as a biomarker in Cancerseveral mouse lung cancer models .
26894620
In the present investigation we used a primary two-stage initiation and promotion model to test our hypothesis that Ereg deficiency would reduce Cancerlung tumor promotion in mice .
26894620
We used 3-methylcholanthrene ( initiator ) or oil vehicle followed by multiple weekly exposures to butylated hydroxytoluene ( BHT ; promoter ) in mice lacking Ereg ( Ereg (-/-) ) and wildtype controls ( BALB and ByJ ; Ereg ( +/+ ) ) and examined multiple time points and endpoints ( bronchoalveolar lavage analysis , Cancertumor analysis , mRNA expression , ELISA , wound assay ) during tumor promotion .
26894620
We used 3-methylcholanthrene ( initiator ) or oil vehicle followed by multiple weekly exposures to butylated hydroxytoluene ( BHT ; promoter ) in mice lacking Ereg ( Ereg (-/-) ) and wildtype controls ( BALB and ByJ ; Ereg ( +/+ ) ) and examined multiple time points and endpoints ( bronchoalveolar lavage analysis , tumor analysis , mRNA expression , ELISA , wound assay ) during Cancertumor promotion .
26894620
At the early time points ( 4 and 12wk ) , we observed significantly reduced amounts of Diseaseinflammation ( macrophages , PMNs ) in the Ereg (-/-) mice compared to controls ( Ereg ( +/+ ) ) .
26894620
At 20wk , Cancertumor multiplicity was also significantly decreased in the Ereg (-/-) mice versus controls ( Ereg ( +/+ ) ) .
26894620
IL10 expression , an anti-inflammatory mediator , and downstream signaling events ( Stat3 ) were significantly increased in the Ereg (-/-) mice in response to BHT , supporting both reduced Diseaseinflammation and tumorigenesis .
26894620
These results indicate that Ereg has proliferative potential and may be utilized as an Cancerearly cancer biomarker as well as a novel potential therapeutic target .
26894859
CancerMeningiomas are frequent central nervous system tumors .
26894859
Meningiomas are Cancerfrequent central nervous system tumors .
26894859
Although Cancermost meningiomas are benign ( WHO grade I ) and curable by surgery , WHO grade II and III tumors remain therapeutically challenging due to frequent recurrence .
26894859
Although most meningiomas are benign ( WHO grade I ) and curable by surgery , WHO grade II and III Cancertumors remain therapeutically challenging due to frequent recurrence .
26894859
Interestingly , relapse also occurs in some WHO grade I Cancermeningiomas .
26894859
Hence , we investigated the transcriptional features defining aggressive ( recurrent , malignantly progressing or WHO grade III ) Cancermeningiomas in 144 cases .
26894859
CancerMeningiomas were categorized into non recurrent ( NR ) , recurrent ( R ) , and tumors undergoing malignant progression ( M ) in addition to their WHO grade .
26894859
Meningiomas were categorized into non recurrent ( NR ) , recurrent ( R ) , and Cancertumors undergoing malignant progression ( M ) in addition to their WHO grade .
26894859
Unsupervised transcriptomic analysis in 62 Cancermeningiomas revealed transcriptional profiles lining up according to WHO grade and clinical subgroup .
26894859
Notably aggressive subgroups ( CancerR+M tumors and WHO grade III ) shared a large set of differentially expressed genes ( n = 332 ; p < 0.01 , FC > 1.25 ) .
26894859
Additionally , among WHO grade I Cancertumors differential expression between NR and aggressive R+M tumors was affirmed for PTTG1 , AURKB , ECT2 , UBE2C and PRC1 , while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors .
26894859
Additionally , among WHO grade I tumors differential expression between NR and Canceraggressive R+M tumors was affirmed for PTTG1 , AURKB , ECT2 , UBE2C and PRC1 , while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors .
26894859
Additionally , among WHO grade I tumors differential expression between NR and aggressive R+M tumors was affirmed for PTTG1 , AURKB , ECT2 , UBE2C and PRC1 , while MN1 and LEPR discriminated between NR and R+M WHO grade II Cancertumors .
26894859
Finally , stainings of PTTG1 and LEPR confirmed Cancermalignancy associated protein expression changes .
26894859
In conclusion , based on the so far largest study sample of WHO grade III and Cancerrecurrent meningiomas we report a comprehensive transcriptional landscape and two prognostic markers .
26894977
CancerGastric adenocarcinoma is a common form of cancer associated with a poor prognosis .
26894977
Gastric adenocarcinoma is a common form of Cancercancer associated with a poor prognosis .
26894977
Gastric adenocarcinoma is a common form of cancer associated with a AdverseOutcomepoor prognosis .
26894977
We analyzed microarray profiling data from 48 patients with Cancergastric adenocarcinoma to characterize gastric cancer subtypes and identify biomarkers associated with prognosis .
26894977
We analyzed microarray profiling data from 48 patients with gastric adenocarcinoma to characterize Cancergastric cancer subtypes and identify biomarkers associated with prognosis .
26894977
We identified two major subtypes of Cancergastric adenocarcinoma differentially associated with overall survival ( P = 0.025 ) .
26894977
Genes that were differentially expressed were identified using specific criteria ( P < 0.001 and > 1.5-fold ) ; expression of 294 and 116 genes was enriched in good and AdverseOutcomepoor prognosis subtypes , respectively .
26894977
Genes related to translational elongation and cell cycle were upregulated in the AdverseOutcomepoor prognosis group .
26894977
PSMB8 or PBK knockdown had no effect on Cancergastric cancer cell proliferation but suppressed cell migration and invasion , respectively .
26894977
Furthermore , immunohistochemistry analysis of 385 Cancergastric cancer patients revealed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion , lymph node metastasis , and lower survival rates .
26894977
Furthermore , immunohistochemistry analysis of 385 gastric cancer patients revealed that increased nuclear expression of PSMB8 and PBK was correlated with depth of invasion , Cancerlymph node metastasis , and lower survival rates .
26894977
Taken together , two Cancergastric adenocarcinoma subtypes were predictive of prognosis .
26894977
PSMB8 and PBK were predictive of Cancergastric cancer prognosis and could be potential gastric cancer subtype specific biomarkers .
26894977
PSMB8 and PBK were predictive of gastric cancer prognosis and could be Cancerpotential gastric cancer subtype specific biomarkers .
26899019
INTRODUCTION : CancerTumor protein p53 gene ( TP53 ) mutations are common in stage I through III non small cell lung cancer , but clinical trials have shown inconsistent results regarding their relationship to the effects of adjuvant therapy .
26899019
INTRODUCTION : Tumor protein p53 gene ( TP53 ) mutations are common in stage I through III Cancernon small cell lung cancer , but clinical trials have shown inconsistent results regarding their relationship to the effects of adjuvant therapy .
26899019
METHODS : A pooled analysis of TP53 mutations ( exons 5-8 ) was conducted in four randomized trials ( the CancerInternational Adjuvant Lung Cancer Trial , J BRonchus 10 , Cancer and Leukemia Group B-9633 , and Adjuvant Navelbine International TrialistAssociation trial ) of platinum based adjuvant chemotherapy ( ACT ) versus observation ( OBS ) .
26899019
METHODS : A pooled analysis of TP53 mutations ( exons 5-8 ) was conducted in four randomized trials ( the International Adjuvant Lung Cancer Trial , J BRonchus 10 , CancerCancer and Leukemia Group B-9633 , and Adjuvant Navelbine International TrialistAssociation trial ) of platinum based adjuvant chemotherapy ( ACT ) versus observation ( OBS ) .
26899019
METHODS : A pooled analysis of TP53 mutations ( exons 5-8 ) was conducted in four randomized trials ( the International Adjuvant Lung Cancer Trial , J BRonchus 10 , Cancer and DiseaseLeukemia Group B-9633 , and Adjuvant Navelbine International TrialistAssociation trial ) of platinum based adjuvant chemotherapy ( ACT ) versus observation ( OBS ) .
26916894
PURPOSE : Adequate biomarkers are still required to optimize therapy in patients with locally advanced head and Cancerneck squamous carcinomas ( HNSCC ) treated with chemoradiotherapy ( CRT ) .
26918046
Increasing evidence indicates that aberrant expression of PIM1 , p-STAT3 and c-MYC is involved in the pathogenesis of Cancervarious solid tumors , but its prognostic value is still unclear in non small cell lung cancer ( NSCLC ) .
26918046
Increasing evidence indicates that aberrant expression of PIM1 , p-STAT3 and c-MYC is involved in the pathogenesis of various solid tumors , but its prognostic value is still unclear in Cancernon small cell lung cancer ( NSCLC ) .
26918046
Here , we sought to evaluate the expression and prognostic role of these markers in patients with Cancerlung adenocarcinoma ( AD ) and squamous cell carcinoma ( SCC ) .
26918046
Here , we sought to evaluate the expression and prognostic role of these markers in patients with lung adenocarcinoma ( AD ) and Cancersquamous cell carcinoma ( SCC ) .
26918046
The expression of PIM1 , p-STAT3 , and c-MYC was immunohistochemically tested in Cancerarchival tumor samples from 194 lung AD and SCC patients .
26918046
High nuclear PIM1 expression was detected in 43.3 % of ADs and SCCs , and was significantly correlated with lymph node ( LN ) Cancermetastasis ( P = 0.028 ) and histology ( P = 0.003 ) .
26918046
High p-STAT3 expression was not associated with OS but significantly correlated with CancerLN metastasis , while c-MYC was not significantly correlated with any clinicopathological parameter or survival .
26918451
BACKGROUND : Clinical trials of immune checkpoints modulators , including both programmed cell death-1 ( PD-1 ) and programmed cell death-ligand 1 ( PD-L1 ) inhibitors , have recently shown promising activity and Diseasetolerable toxicity in pre-treated NSCLC patients .
26918451
This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1 and PD-L1 monoclonal antibodies ( MoAbs ) and Cancertumor PD-L1 expression in pre-treated NSCLC patients .
26918451
METHODS : Data from published studies , that evaluated efficacy and safety of PD-1 and PD-L1 inhibitors in pre-treated NSCLC patients , stratified by Cancertumor PD-L1 expression status ( immunohistochemistry , cut-off point 1 % ) , were collected by searching in PubMed , Cochrane Library , American Society of Clinical Oncology , European Society of Medical Oncology and World Conference of Lung Cancer , meeting proceedings .
26918451
METHODS : Data from published studies , that evaluated efficacy and safety of PD-1 and PD-L1 inhibitors in pre-treated NSCLC patients , stratified by tumor PD-L1 expression status ( immunohistochemistry , cut-off point 1 % ) , were collected by searching in PubMed , Cochrane Library , American Society of Clinical Oncology , European Society of Medical Oncology and World Conference of CancerLung Cancer , meeting proceedings .
26918451
Pooled Odds ratio ( OR ) and 95 % confidence intervals ( 95 % CIs ) were calculated for the Overall Response Rate ( ORR ) ( as evaluated by Response Evaluation Criteria in CancerSolid Tumors , version 1.1 ) , according to PD-L1 expression status .
26918451
Pooled analysis showed that patients with CancerPD-L1 positive tumors ( PD-L1 tumor cell staining > = 1 % ) , had a significantly higher ORR , compared to patients with PD-L1 negative tumors ( OR : 2.44 ; 95 % CIs : 1.61-3 .68 ) .
26918451
Pooled analysis showed that patients with PD-L1 positive tumors ( CancerPD-L1 tumor cell staining > = 1 % ) , had a significantly higher ORR , compared to patients with PD-L1 negative tumors ( OR : 2.44 ; 95 % CIs : 1.61-3 .68 ) .
26918451
Pooled analysis showed that patients with PD-L1 positive tumors ( PD-L1 tumor cell staining > = 1 % ) , had a significantly higher ORR , compared to patients with CancerPD-L1 negative tumors ( OR : 2.44 ; 95 % CIs : 1.61-3 .68 ) .
26918451
CONCLUSIONS : CancerPD-L1 tumor over-expression seems to be associated with higher clinical activity of anti PD-1 and PD-L1 MoAbs , in pre-treated NSCLC patients , suggesting a potential role of PD-L1 expression , IHC cut-off point 1 % , as predictive biomarker for the selection of patients to treat with immune-checkpoint inhibitors .
26920887
PURPOSE : CancerHER2 positive breast cancer is heterogeneous .
26920887
Some Cancertumors express mutations , like activating PIK3CA mutations or reduced PTEN expression , that negatively correlate with response to HER2 targeted therapies .
26920887
EXPERIMENTAL DESIGN : CancerTumors were evaluated for HER2 ( n = 866 ) , EGFR ( n = 832 ) , and HER3 ( n = 860 ) mRNA expression by quantitative reverse transcriptase PCR ; for PTEN protein expression ( n = 271 ) by IHC ; and for PIK3CA mutations ( n = 259 ) using a mutation detection kit .
26920887
T-DM1 was also tested on cell lines and in Cancerbreast cancer xenograft models containing PIK3CA mutations .
26920887
CONCLUSIONS : Although other standard HER2 directed therapies are less effective in Cancertumors with PI3KCA mutations , T-DM1 appears to be effective in both PI3KCA mutated and wild-type tumors .
26920887
CONCLUSIONS : Although other standard HER2 directed therapies are less effective in tumors with PI3KCA mutations , T-DM1 appears to be effective in both PI3KCA mutated and Cancerwild-type tumors .
26921265
PURPOSE : Addition of bevacizumab to trastuzumab based neoadjuvant chemotherapy in CancerHER2 positive inflammatory breast cancer ( IBC ) was associated with favorable outcome in the BEVERLY-2 phase II trial .
26921265
Circulating levels of matrix metalloproteinases ( MMP ) 2 and 9 were correlated to high response rate and prolonged survival in Cancerhigh-grade glioma treated with bevacizumab .
26921265
RESULTS : Baseline ( b ) MMP2 and MMP9 serum levels were independent from patient characteristics and circulating Cancertumor or endothelial cells , and were not correlated to pCR .
26936505
Recent work in Cancerhuman glioblastoma ( GBM ) has documented recurrent mutations in the histone chaperone protein ATRX .
26936505
Further , analysis of genome-wide data for Cancerhuman gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant ( SNV ) level .
26936505
In Cancermouse tumors , ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA damaging agents that induce double stranded DNA breaks .
26936505
We propose that ATRX loss results in a genetically Cancerunstable tumor , which is more aggressive when left untreated but is more responsive to double stranded DNA damaging agents , resulting in improved overall survival .
26938871
CancerAnaplastic lymphoma kinase ( ALK ) tyrosine kinase inhibitors ( TKIs ) have shown promising clinical activity in the treatment of non-small-cell lung cancer ( NSCLC ) that harbors ALK rearrangement .
26938871
Anaplastic lymphoma kinase ( ALK ) tyrosine kinase inhibitors ( TKIs ) have shown promising clinical activity in the treatment of Cancernon-small-cell lung cancer ( NSCLC ) that harbors ALK rearrangement .
26943774
In Cancercancer , HSP promotes the survival of malignant cells by inhibiting the induction of apoptosis .
26943774
In Cancercolorectal cancer , a loss-of-function mutation of HSP110 ( HSP110DeltaE9 ) has been identified .
26943774
There is still insufficient information about HSP110 localization , the clinicopathological significance of HSP110 expression , and its association with chemotherapy resistance in Cancergastric cancer .
26943774
Here , we found that high nuclear expression of HSP110 in Cancergastric cancer tissues is associated with cancer progression , poor prognosis , and recurrence after adjuvant chemotherapy .
26943774
Here , we found that high nuclear expression of HSP110 in gastric cancer tissues is associated with Cancercancer progression , poor prognosis , and recurrence after adjuvant chemotherapy .
26943774
Here , we found that high nuclear expression of HSP110 in gastric cancer tissues is associated with cancer progression , AdverseOutcomepoor prognosis , and recurrence after adjuvant chemotherapy .
26943774
In vitro results showed that HSP110 suppression increases the sensitivity to 5-fluorouracil and cisplatin of Cancerhuman gastric cancer cell lines .
26943774
Our results suggest that nuclear HSP110 may be a new drug sensitivity marker for Cancergastric cancer and a potential molecular therapeutic target for the treatment of gastric cancer patients with acquired anticancer drug resistance .
26943774
Our results suggest that nuclear HSP110 may be a new drug sensitivity marker for gastric cancer and a potential molecular therapeutic target for the treatment of Cancergastric cancer patients with acquired anticancer drug resistance .
26950277
Activin A ( ActA )/follistatin ( FST ) signaling has been shown to be deregulated in Cancerdifferent tumor types including lung adenocarcinoma ( LADC ) .
26950277
Activin A ( ActA )/follistatin ( FST ) signaling has been shown to be deregulated in different tumor types including Cancerlung adenocarcinoma ( LADC ) .
26950277
ActA levels also correlated with Diseasemore advanced disease stage ( p < 0.0001 ) and T ( p = 0.0035 ) and N ( p = 0.0002 ) factors .
26956051
Numerous antiangiogenic agents are approved for the treatment of Diseaseoncological diseases .
26956051
Therefore , the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with Cancerhepatocellular cancer ( n = 11 ) , renal cell cancer ( n = 7 ) and non small cell lung cancer ( n = 2 ) .
26956051
Therefore , the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer ( n = 11 ) , Cancerrenal cell cancer ( n = 7 ) and non small cell lung cancer ( n = 2 ) .
26956051
Therefore , the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer ( n = 11 ) , renal cell cancer ( n = 7 ) and Cancernon small cell lung cancer ( n = 2 ) .
26956051
Thereby we measured levels of angiogenic growth factors , Cancertumor perfusion , circulating endothelial cells ( CEC ) , circulating endothelial progenitor cells ( CEP ) and tumor endothelial markers ( TEM ) in patients during the course of therapy with antiangiogenic agents , and correlated them with the time to antiangiogenic progression ( aTTP ) .
26956051
Thereby we measured levels of angiogenic growth factors , tumor perfusion , circulating endothelial cells ( CEC ) , circulating endothelial progenitor cells ( CEP ) and Cancertumor endothelial markers ( TEM ) in patients during the course of therapy with antiangiogenic agents , and correlated them with the time to antiangiogenic progression ( aTTP ) .
26956051
Importantly , at Diseasedisease progression , we observed an increase of proangiogenic factors , upregulation of CEC and CEP levels and downregulation of TEMs , such as Robo4 and endothelial cell specific chemotaxis regulator ( ECSCR ) , reflecting the formation of torturous tumor vessels .
26956051
Importantly , at disease progression , we observed an increase of proangiogenic factors , upregulation of CEC and CEP levels and downregulation of TEMs , such as Robo4 and endothelial cell specific chemotaxis regulator ( ECSCR ) , reflecting the formation of Cancertorturous tumor vessels .
26956051
Higher TEM expression during Diseasedisease progression may have clinical and pathophysiological implications , however , validation of our results is warranted for further biomarker development .
26970723
BACKGROUND : Outcomes are poor for patients with previously treated , advanced or Cancermetastatic non-small-cell lung cancer ( NSCLC ) .
26970723
The anti-programmed death ligand 1 ( PD-L1 ) antibody atezolizumab is clinically active against Cancercancer , including NSCLC , especially cancers expressing PD-L1 on tumour cells , tumour infiltrating immune cells , or both .
26970723
The anti-programmed death ligand 1 ( PD-L1 ) antibody atezolizumab is clinically active against cancer , including NSCLC , especially Cancercancers expressing PD-L1 on tumour cells , tumour infiltrating immune cells , or both .
26970723
The anti-programmed death ligand 1 ( PD-L1 ) antibody atezolizumab is clinically active against cancer , including NSCLC , especially cancers expressing PD-L1 on Cancertumour cells , tumour infiltrating immune cells , or both .
26970723
The anti-programmed death ligand 1 ( PD-L1 ) antibody atezolizumab is clinically active against cancer , including NSCLC , especially cancers expressing PD-L1 on tumour cells , Cancertumour infiltrating immune cells , or both .
26970723
We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC , analysed by PD-L1 expression levels on Cancertumour cells and tumour infiltrating immune cells and in the intention-to-treat population .
26970723
We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC , analysed by PD-L1 expression levels on tumour cells and Cancertumour infiltrating immune cells and in the intention-to-treat population .
26970723
Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1 , Diseasemeasurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 ( RECIST v1 .1 ) , and adequate haematological and end-organ function .
26970723
Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1 , measurable disease by Response Evaluation Criteria In CancerSolid Tumors version 1.1 ( RECIST v1 .1 ) , and adequate haematological and end-organ function .
26970723
Patients were stratified by CancerPD-L1 tumour infiltrating immune cell status , histology , and previous lines of therapy , and randomly assigned ( 1:1 ) by permuted block randomisation ( with a block size of four ) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m ( 2 ) once every 3 weeks .
26970723
Baseline PD-L1 expression was scored by immunohistochemistry in Cancertumour cells ( as percentage of PD-L1-expressing tumour cells TC3 > = 50 % , TC2 > = 5 % and < 50 % , TC1 > = 1 % and < 5 % , and TC0 < 1 % ) and tumour infiltrating immune cells ( as percentage of tumour area : IC3 > = 10 % , IC2 > = 5 % and < 10 % , IC1 > = 1 % and < 5 % , and IC0 < 1 % ) .
26970723
Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells ( as percentage of CancerPD-L1-expressing tumour cells TC3 > = 50 % , TC2 > = 5 % and < 50 % , TC1 > = 1 % and < 5 % , and TC0 < 1 % ) and tumour infiltrating immune cells ( as percentage of tumour area : IC3 > = 10 % , IC2 > = 5 % and < 10 % , IC1 > = 1 % and < 5 % , and IC0 < 1 % ) .
26970723
Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells ( as percentage of PD-L1-expressing tumour cells TC3 > = 50 % , TC2 > = 5 % and < 50 % , TC1 > = 1 % and < 5 % , and TC0 < 1 % ) and Cancertumour infiltrating immune cells ( as percentage of tumour area : IC3 > = 10 % , IC2 > = 5 % and < 10 % , IC1 > = 1 % and < 5 % , and IC0 < 1 % ) .
26970723
Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells ( as percentage of PD-L1-expressing tumour cells TC3 > = 50 % , TC2 > = 5 % and < 50 % , TC1 > = 1 % and < 5 % , and TC0 < 1 % ) and tumour infiltrating immune cells ( as percentage of Cancertumour area : IC3 > = 10 % , IC2 > = 5 % and < 10 % , IC1 > = 1 % and < 5 % , and IC0 < 1 % ) .
26970723
Improvement correlated with PD-L1 immunohistochemistry expression on Cancertumour cells and tumour infiltrating immune cells , suggesting that PD-L1 expression is predictive for atezolizumab benefit .
26970723
Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and Cancertumour infiltrating immune cells , suggesting that PD-L1 expression is predictive for atezolizumab benefit .
26973324
BACKGROUND : ALK rearranged Cancernon-small-cell lung cancer ( NSCLC ) is sensitive to ALK tyrosine kinase inhibitors ( ALK inhibitors ) such as crizotinib , but resistance invariably develops , often with progression in the brain .
26973324
Ceritinib is a more potent ALK inhibitor than crizotinib in vitro , crosses the blood-brain barrier in vivo , and shows clinical responses in patients with Diseasecrizotinib resistant disease .
26973324
METHODS : ASCEND-1 was an open-label , phase 1 trial that recruited patients from 20 academic hospitals or Cancercancer centres in 11 countries in Europe , North America , and Asia-Pacific .
26973324
Eligible patients were aged 18 years or older with ALK rearranged locally advanced or Cancermetastatic cancer that had progressed despite standard therapy ( or for which no effective standard therapy existed ) , who had at least one measurable lesion at baseline .
26973324
At data cutoff ( April 14 , 2014 ) , median follow-up was 11.1 months ( IQR 6.7-15 .2 ) and 147 ( 60 % ) patients had discontinued treatment , 98 ( 40 % ) as a result of Diseasedisease progression .
26973324
Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CancerCT tumour assessment , intracranial disease control was reported in 15 ( 79 % [ 95 % CI 54-94 ] ) of 19 ALK inhibitor-naive patients and in 49 ( 65 % [ 54-76 ] ) of 75 ALK inhibitor pretreated patients .
26973324
Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment , Diseaseintracranial disease control was reported in 15 ( 79 % [ 95 % CI 54-94 ] ) of 19 ALK inhibitor-naive patients and in 49 ( 65 % [ 54-76 ] ) of 75 ALK inhibitor pretreated patients .
26973324
Two on-treatment deaths during the study were deemed to be related to study drug by the investigators , one due to Diseaseinterstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis .
26973324
Two on-treatment deaths during the study were deemed to be related to study drug by the investigators , one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of Diseaseinfection and ischaemic hepatitis .
26973324
Two on-treatment deaths during the study were deemed to be related to study drug by the investigators , one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and Diseaseischaemic hepatitis .
26979979
PURPOSE : In this paper , we aimed to collect genetic and medical information on all Danish patients with DiseasePeutz-Jeghers syndrome ( PJS ) , in order to contribute to the knowledge of phenotype and genotype .
26979979
DiseasePeutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract , mucocutaneous pigmentations , and an increased risk of cancer in the GI tract and at extraintestinal sites .
26979979
Peutz-Jeghers syndrome is a Diseasehereditary syndrome characterized by multiple hamartomatous polyps in the GI tract , mucocutaneous pigmentations , and an increased risk of cancer in the GI tract and at extraintestinal sites .
26979979
Peutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract , mucocutaneous pigmentations , and an AdverseOutcomeincreased risk of cancer in the GI tract and at extraintestinal sites .
26979979
Peutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract , mucocutaneous pigmentations , and an increased risk of Cancercancer in the GI tract and at extraintestinal sites .
26979979
We noted 18 occurrences of Cancercancer at various anatomical sites , including a case of thyroid cancer and penile cancer .
26979979
We noted 18 occurrences of cancer at various anatomical sites , including a case of Cancerthyroid cancer and penile cancer .
26979979
We noted 18 occurrences of cancer at various anatomical sites , including a case of thyroid cancer and Cancerpenile cancer .
26979979
Eight of the deceased patients had died of Cancercancer .
26979979
CONCLUSION : This is the first comprehensive study of patients with DiseasePeutz-Jeghers syndrome in the Danish population identified from nationwide registers and databases .
26979979
We have demonstrated that the expressivity of DiseasePeutz-Jeghers syndrome varies greatly among the patients , even within the same families , underlining the great phenotypic spectrum .
26979979
Patients with PJS should be offered surveillance from childhood in order to prevent morbidity and reduce AdverseOutcomemortality .
26989536
BRAF kinase inhibitors such as Vemurafenib have shown improvement in overall survival , progression-free survival , and response rates in patients with Cancermetastatic melanoma with BRAF V600K mutation .
26989536
A 53-year-old man with Cancermetastatic melanoma and dialysis dependent end stage renal failure was treated safely with Vemurafenib for a BRAF V600K mutation positive melanoma and the case was reported elsewhere .
26989536
A 53-year-old man with metastatic melanoma and dialysis dependent end stage renal failure was treated safely with Vemurafenib for a CancerBRAF V600K mutation positive melanoma and the case was reported elsewhere .
26989536
DiseaseMain toxicities reported were grade 1 photosensitivity and skin cancers .
26989536
Main toxicities reported were grade 1 photosensitivity and Cancerskin cancers .
26989536
Vemurafenib was discontinued but patient remains Diseasedisease free 12 months after stopping treatment and the clinical review is ongoing .
26989536
This is the first reported case of complete radiological response to a BRAF inhibitor in Cancermetastatic melanoma with BRAF V600K mutation and remains disease free even after discontinuation of treatment .
26989536
This is the first reported case of complete radiological response to a BRAF inhibitor in metastatic melanoma with BRAF V600K mutation and remains Diseasedisease free even after discontinuation of treatment .
26989536
This also shows clinical safety of Vemurafenib in end stage renal failure and highlights the need for closer look at the subgroup of patients with BRAF V600K mutation and its Cancertumour biology .
27001570
PURPOSE : CancerRecurrent glioblastoma multiforme ( GBM ) is incurable with current therapies .
27001570
Biallelic mismatch repair deficiency ( bMMRD ) is a highly Cancerpenetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden .
27001570
Biallelic mismatch repair deficiency ( bMMRD ) is a highly Diseasepenetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden .
27001570
PATIENTS AND METHODS : We performed exome sequencing and neoantigen prediction on 37 CancerbMMRD cancers and compared them with childhood and adult brain neoplasms .
27001570
Neoantigen prediction bMMRD GBM was compared with Cancerresponsive adult cancers from multiple tissues .
27001570
RESULTS : All Cancermalignant tumors ( n = 32 ) were hypermutant .
27001570
Although CancerbMMRD brain tumors had the highest mutational load because of secondary polymerase mutations ( mean , 17,740 +/- standard deviation , 7,703 ) , all other high-grade tumors were hypermutant ( mean , 1,589 +/- standard deviation , 1,043 ) , similar to other cancers that responded favorably to immune checkpoint inhibitors .
27001570
Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations ( mean , 17,740 +/- standard deviation , 7,703 ) , all Cancerother high-grade tumors were hypermutant ( mean , 1,589 +/- standard deviation , 1,043 ) , similar to other cancers that responded favorably to immune checkpoint inhibitors .
27001570
Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations ( mean , 17,740 +/- standard deviation , 7,703 ) , all other high-grade tumors were hypermutant ( mean , 1,589 +/- standard deviation , 1,043 ) , similar to Cancerother cancers that responded favorably to immune checkpoint inhibitors .
27001570
bMMRD GBM had a significantly higher mutational load than sporadic pediatric and Canceradult gliomas and all other brain tumors ( P < .001 ) .
27001570
bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all Cancerother brain tumors ( P < .001 ) .
27001570
bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in Cancerimmunoresponsive melanomas , lung cancers , or microsatellite-unstable GI cancers ( P < .001 ) .
27001570
bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas , Cancerlung cancers , or microsatellite-unstable GI cancers ( P < .001 ) .
27001570
bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas , lung cancers , or Cancermicrosatellite-unstable GI cancers ( P < .001 ) .
27001570
CONCLUSION : This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and Cancerother hypermutant cancers arising from primary ( genetic predisposition ) or secondary MMRD .
27004155
This is the case of an 84-year-old woman diagnosed with CancerStage IVb colon adenocarcinoma ( CRC ) metastatic to the liver , retroperitoneum , anastomotic site , and distal rectal sigmoid colon .
27004155
She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab , as well as Diseasedisease progression .
27004155
Next generation sequencing of her Cancertumor was ordered , and further discussion of her malignancy 's genomic information took place at a multidisciplinary molecular tumor board .
27004155
Next generation sequencing of her tumor was ordered , and further discussion of her Cancermalignancy 's genomic information took place at a multidisciplinary molecular tumor board .
27004155
Next generation sequencing of her tumor was ordered , and further discussion of her malignancy 's genomic information took place at a Cancermultidisciplinary molecular tumor board .
27004155
The patient had mutations in KRAS ( CancerKirsten rat sarcoma viral oncogene homolog ) which made her ineligible for epidermal growth factor receptor ( EGFR ) inhibitors ; however , a KDR p.R961W c. 2881C > T mutation was noted as a variant of unknown significance ( VUS ) .
27004155
We report her excellent tolerance and exceptional response to low dose regorafenib , including symptomatic , Cancertumor marker , and sustained partial metabolic radiological improvement .
27009855
Targeting the PD-1 and PD-L1 immune checkpoint signaling is a novel promising treatment strategy in Cancerseveral tumor entities , and it is suggested that PD-L1 and PD-1 expression is predictive for a PD-1 and PD-L1 checkpoint inhibitor treatment response .
27009855
We investigated the expression of PD-L1 and PD-1 by immunohistochemistry in a large and well characterized Cancergastric cancer ( GC ) cohort of Caucasian patients , consisting of 465 GC samples and 15 corresponding liver metastases .
27009855
PD-L1 expression was found in Cancertumor cells of 140 GCs ( 30.1 % ) and 9 liver metastases ( 60 % ) respectively in immune cells of 411 GCs ( 88.4 % ) and 11 liver metastases ( 73.3 % ) .
27009855
PD-1 was expressed in Cancertumor infiltrating lymphocytes in 250 GCs ( 53.8 % ) and in 11 liver metastases ( 73.3 % ) .
27010960
OBJECTIVES : There is no molecular biomarker available in the clinical practice to assess the prognosis of Canceradvanced pancreatic carcinoma .
27010960
This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the Cancerprimary tumor to determine the prognosis of advanced pancreatic cancer .
27010960
This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of Canceradvanced pancreatic cancer .
27010960
METHODS : The exon-2 KRAS mutation status was tested on endoscopic ultrasound guided fine-needle aspiration biopsy material ( Cancerprimary tumor ; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination ) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma .
27010960
METHODS : The exon-2 KRAS mutation status was tested on endoscopic ultrasound guided fine-needle aspiration biopsy material ( primary tumor ; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination ) of patients with proven locally advanced and/or Cancermetastatic pancreatic ductal carcinoma .
27010960
We used the Kaplan-Meier method , log-rank test , and Cox 's model to evaluate the impact of KRAS status on the overall survival ( OS ) , adjusting for age , stage of Diseasedisease , clinical performance status , CA 19-9 levels , and treatment .
27010960
CONCLUSIONS : The KRAS G12D mutation subtype is an independent prognostic marker for Canceradvanced pancreatic ductal carcinoma .
27019113
The oncogenic mechanisms underlying Canceracute lymphoblastic leukemia ( ALL ) in adolescents and young adults ( AYA ; 15-39 years old ) remain largely elusive .
27019113
A transplantation assay in mice demonstrated that expression of DUX4-IGH in pro B cells was capable of generating CancerB cell leukemia in vivo .
27020857
Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor ( CancerER )-positive metastatic breast cancer , although their cytostatic effects are limited by primary and acquired resistance .
27020857
Here we report that CancerER positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis , in part , via noncanonical cyclin D1-CDK2-mediated S-phase entry .
27020857
Combined targeting of both CDK4/6 and PI3K triggered Cancercancer cell apoptosis in vitro and in patient derived tumor xenograft ( PDX ) models , resulting in tumor regression and improved disease control .
27020857
Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient derived Cancertumor xenograft ( PDX ) models , resulting in tumor regression and improved disease control .
27020857
Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient derived tumor xenograft ( PDX ) models , resulting in Cancertumor regression and improved disease control .
27020857
Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient derived tumor xenograft ( PDX ) models , resulting in tumor regression and improved Diseasedisease control .
27020857
Furthermore , a triple combination of endocrine therapy , CDK4/6 , and PI3K inhibition was more effective than paired combinations , provoking Cancerrapid tumor regressions in a PDX model .
27020857
CancerCancer Res ; 76 ( 8 ) ; 2301-13 .
27022066
BACKGROUND : A patient suffering from Cancermetastatic colorectal cancer , treatment related toxicity and resistance to standard chemotherapy and radiation was assessed as part of a personalized oncogenomics initiative to derive potential alternative therapeutic strategies .
27022066
BACKGROUND : A patient suffering from metastatic colorectal cancer , Diseasetreatment related toxicity and resistance to standard chemotherapy and radiation was assessed as part of a personalized oncogenomics initiative to derive potential alternative therapeutic strategies .
27022066
PATIENTS AND METHODS : Whole-genome and transcriptome sequencing was used to interrogate a Cancermetastatic tumor refractory to standard treatments of a patient with mismatch repair deficient metastatic colorectal cancer .
27022066
PATIENTS AND METHODS : Whole-genome and transcriptome sequencing was used to interrogate a metastatic tumor refractory to standard treatments of a patient with Cancermismatch repair deficient metastatic colorectal cancer .
27022118
PURPOSE : Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in CancerALK positive non-small-cell lung cancer .
27022118
Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases ( BM ) , respectively ; intracranial time to Cancertumor progression ( IC-TTP ; per protocol ) and intracranial disease control rate ( IC-DCR ; post hoc ) were measured .
27022118
Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases ( BM ) , respectively ; intracranial time to tumor progression ( IC-TTP ; per protocol ) and Diseaseintracranial disease control rate ( IC-DCR ; post hoc ) were measured .
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